Pubmed abstracts for Protein-Protein Interaction search result :

Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.65279861
A dimerization domain within PML is able to mediate the formation of PML RAR alpha homodimers that can bind to target sequences with distinct DNA binding properties if compared with RAR alpha . ( ABSTRACT TRUNCATED AT 250 WORDS ) . 0.65279861^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.80121892
Molecular study showed PML RAR alpha can form heterodimers with wild type PML and RXR . 0.80121892^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.51691681
In particular , the demonstration that PML and PLZF can form heterodimers provides a critical functional link between these proteins and offers a tantalizing glimpse at how both , when linked with RAR alpha , can cause APL . 0.51691681^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.61645541
Mut PML interacts with PML RARalpha in PML CB and potentiates PML RARalpha mediated inhibition of RA dependent transcription . 0.61645541^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The retinoic acid receptor alpha ( RAR alpha ) and the myl gene are involved in the translocation breakpoint t ( 15 ; 17 ) ( q 22 ; q 21 ) in acute promyelocytic leukemia ( APL ) . ^^^ The majority of the breakpoint sites have been mapped within the second intron of the RAR alpha gene ; however , the breakpoint sites on the myl gene are variable . ^^^ Using primer sets derived from exon 2 or exon 3 of the RAR alpha gene and a primer derived from the myl cDNA , we were able to amplify the breakpoint sites of the fusion transcripts of all six APL RNA samples by the reverse transcriptase polymerase chain reaction ( RT PCR ) . ^^^ Northern blot analysis demonstrated that fusion transcripts RAR alpha / myl and myl / RAR alpha of varying sizes were detected in patients with different breakpoint sites on the myl gene . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Characterization of a fusion cDNA ( RARA / myl ) transcribed from the t ( 15 ; 17 ) translocation breakpoint in acute promyelocytic leukemia . ^^^ We designate this fusion cDNA RARA / myl , which is different from myl / RARA reported by de The et al . ( H . de The , C . ^^^ Using the polymerase chain reaction , we demonstrated that both RARA / myl and myl / RARA were coexpressed in samples from three different APL patients . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APL ) is due to a chromosomal t ( 15 ; 17 ) translocation which involves a novel human gene , Myl , ( also named PML ) and the retinoic acid ( RA ) receptor alpha ( RAR alpha ) gene . ^^^ In contrast to both Myl and RAR alpha whose localization is essentially nuclear in the presence or absence of RA , MylRAR which is largely cytoplasmic in the absence of RA appears to be translocated to the nucleus in the presence of RA . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Genomic DNA probes generated from the retinoic acid receptor alpha ( RARA ) gene located on chromosome 17 and from the MYL gene located on chromosome 15 were used to study the chromosome 15 breakpoints resulting from the t ( 15 ; 17 ) translocation in 26 patients with acute promyelocytic leukemia ( APL ) . ^^^ The two remaining patients exhibited a more 5 ' rearrangement at about 10 kb upstream of the MYLbcr region , implying the lack of at least one MYL gene exon in the resulting MYL RARA fusion gene . ^^^ The variation of chromosome breakpoints within the MYL gene may explain size heterogeneity previously observed in some MYL RARA fusion transcripts expressed in APL cells . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
PML / RAR alpha rearrangement in acute promyelocytic leukaemias apparently lacking the t ( 15 ; 17 ) translocation . ^^^ Together with providing new insights into the pathogenesis of the disease , the identification of breakpoints within the RAR alpha and PML loci on chromosomes 17 and 15 has allowed a new relevant diagnostic tool for the recognition of this leukaemic form . ^^^ DNA rearrangements were documented in all cases at the PML and RAR alpha loci . ^^^ These findings highlight the specificity of PML / RAR alpha rearrangements in APL , whereas the lack of t ( 15 ; 17 ) may be attributed to sub microscopic translocations as well as to the presence of non neoplastic cells undergoing mitosis in the samples examined for karyotype . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Genomic variability and alternative splicing generate multiple PML / RAR alpha transcripts that encode aberrant PML proteins and PML / RAR alpha isoforms in acute promyelocytic leukaemia . ^^^ The acute promyelocytic leukaemia ( APL ) 15 ; 17 translocation generates a PML / RAR alpha chimeric gene which is transcribed as a fusion PML / RAR alpha mRNA . ^^^ Molecular studies on a large series of APLs revealed great heterogeneity of the PML / RAR alpha transcripts due to : ( 1 ) variable breaking of chromosome 15 within three PML breakpoint cluster regions ( bcr 1 , bcr 2 and bcr 3 ) , ( 2 ) alternative splicings of the PML portion and ( 3 ) alternative usage of two RAR alpha polyadenylation sites . ^^^ Nucleotide sequence analysis predicted two types of proteins : multiple PML / RAR alpha and aberrant PML . ^^^ The PML / RAR alpha proteins varied among bcr 1 , 2 and 3 APL cases and within single cases . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Expression pattern of the RAR alpha PML fusion gene in acute promyelocytic leukemia . ^^^ Two chimeric genes , PML RAR alpha and RAR alpha PML , are formed as a consequence of the acute promyelocytic leukemia ( APL ) specific reciprocal translocation of chromosomes 15 and 17 [ t ( 15 ; 17 ) ] . ^^^ PML RAR alpha is expressed as a fusion protein . ^^^ We investigated the organization and expression pattern of the RAR alpha PML gene in a series of APL patients representative of the molecular heterogeneity of the t ( 15 ; 17 ) and found ( 1 ) two types of RAR alpha PML mRNA junctions ( RAR alpha exon 2 / PML exon 4 or RAR alpha exon 2 / PML exon 7 ) that maintain the RAR alpha and PML longest open reading frames aligned and are the result of chromosome 15 breaking at two different sites ; and ( 2 ) 10 different RAR alpha PML fusion transcripts that differ for the assembly of their PML coding exons . ^^^ A RAR alpha PML transcript was present in most , but not all , APL patients . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The replacement of the NH 2 terminal transactivation domain in RAR alpha by the PML putative DNA binding and transactivation domains in the PML / RARA fusion produces a novel chimeric protein which may act to block normal myeloid differentiation through disregulation of the genes normally regulated by either or both of the normal proteins . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Characterization of the PML RAR alpha chimeric product of the acute promyelocytic leukemia specific t ( 15 ; 17 ) translocation . ^^^ The acute promyelocytic leukemia 15 ; 17 chromosomal translocation fuses the PML gene to the RAR alpha locus . ^^^ The resulting chimeric gene encodes for a putative PML RAR alpha fusion protein . ^^^ PML is a putative transcriptional factor and RAR alpha is one of the nuclear retinoic acid receptors through which retinoic acid regulates gene expression . ^^^ In this study , we investigated the retinoid binding and biochemical properties of the PML RAR alpha protein by size exclusion high performance liquid chromatography and immunoblot analysis and compared them with those of normal RAR alpha . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The acute promyelocytic leukemia ( APL ) t ( 15 ; 17 ) translocation generates a myl / retinoic acid receptor alpha ( RAR alpha ) chimeric gene that is transcribed as a fusion myl / RAR alpha messenger RNA . ^^^ Using primer sets derived from RAR alpha and myl cDNAs , we were able to amplify the breakpoint sites of the fusion transcripts of all 35 APL RNA samples by reverse polymerase chain reaction ( PCR ) and nested primer approach of two rounds of amplification . ^^^ We conclude that PCR amplification of the myl / RAR alpha junctions represents the easiest and rapid method for diagnosis and monitoring of the APL clone . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Molecular characterization of the t ( 15 ; 17 ) translocation has shown that it fuses a previously unknown zinc finger encoding gene , PML , to the RAR alpha , suggesting a link between the molecular mechanism of transformation and of RA dependent differentiation . ^^^ The PML / RAR alpha fusion receptor which is functionally altered may block RA target genes , impair RA mediated differentiation and lead to transformation . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Due to the t ( 15 ; 17 ) RAR alpha gene translocated to a gene PML on chromosome 15 resulting in synthesis of PML / RAR alpha fusion messenger RNA . ^^^ Detection of PML / RAR alpha transcript is now a molecular marker of the disease . ^^^ The abnormal PML / RAR alpha protein exhibits altered transcription activation properties when compared with RAR alpha . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
To investigate leukemogenesis of acute promyelocytic leukemia ( APL ) , we studied the involvements of retinoic acid receptor alpha ( RAR alpha ) and myl genes , and also the frequency of N RAS , K RAS , H RAS , and FMS point mutations in sixteen patients with APL . ^^^ By Southern blot analysis , the rearrangements of RAR alpha gene were detected in 13 patients ( 81 . 2 % ) , and myl gene in 14 ( 87 . 5 % ) . ^^^ Either RAR alpha or myl gene rearrangements were found in all patients including one with normal karyotype . ^^^ These data indicate that myl RAR alpha translocation occurs frequently in APL , whereas RAS and FMS mutations are rare in APL . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The balanced chromosomal translocation t ( 15 ; 17 ) ( q 22 ; q 12 21 ) of this malignancy is now known to involve the nuclear retinoic acid receptor alpha ( RAR alpha ) on the long arm of chromosome 17 and a novel gene on the long arm of chromosome 15 , designated PML ( previously called myl ) . ^^^ A unique fusion mRNA , PML / RAR alpha , is produced . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
This translocation constructs fusion genes between retinoic acid receptor alpha ( RARA ) at 17q21 and PML at 15q22 . ^^^ Breakpoints cluster in limited regions of RARA and PML , and PML / RARA and RARA / PML transcripts can also be detected by RT PCR . ^^^ Although PML / RARA and RARA / PML fusion products are transcribed in APL , PML / RARA may play an important role in the etiology of APL . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
RARA and PML genes in acute promyelocytic leukemia . ^^^ Recently , using molecular biology techniques , a number of laboratories have demonstrated that the gene coding for the retinoic acid receptor alpha ( RARA ) , normally located on chromosome 17 , is disrupted by the t ( 15 ; 17 ) and fused with the PML gene on chromosome 15 . ^^^ The chromosome 17 breaks were mapped consistently within the second intron of the RARA gene while the chromosome 15 breaks were clustered in two limited regions within the PML gene . ^^^ Different isoforms of the PML RARA fusion transcripts were discovered which are produced as a result of distinct PML gene rearrangements . ^^^ The RT / PCR procedure has been established to characterize the expression patterns of the PML RARA fusion gene and to detect minimal residual disease ( MRD ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The recent cloning of the breakpoints by three groups has demonstrated that the retinoic acid receptor alpha gene ( RARA ) on chromosome 17 is fused to a previously undescribed transcription factor gene , PML , on chromosome 15 . ^^^ The DNA binding motifs of both the RARA and PML proteins , together with the ligand binding domain of RARA , are combined in a single fusion protein which may dysregulate either retinoic acid or PML sensitive pathways . ^^^ Intriguingly , some APLs not only express the PML RARA fusion protein but also the reciprocal RARA PML fusion protein , although the contribution of this product is unclear . ^^^ The PML RARA chimaeric protein is presumably the target during the striking differentiation therapy achieved with all trans retinoic acid . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The characteristic t ( 15 ; 17 ) of acute promyelocytic leukemia ( APL ) fuses the retinoic acid receptor alpha ( RAR alpha ) gene on chromosome 17 to a gene on chromosome 15 called PML , a putative transcription factor . ^^^ This study describes a reverse transcription polymerase chain reaction ( RT PCR ) assay for the PML / RAR alpha fusion transcript , which amplifies PML / RAR alpha mRNA from APL cells with either reported breakpoint . ^^^ DNA sequencing of the predominant RT PCR products from 6 patients showed identical RAR alpha exonic breakpoints and two PML breakpoints . ^^^ Dilutional studies with leukemic cells that express ( NB 4 ) or do not express ( HL 60 ) a PML / RAR alpha fusion mRNA reveal that this RT PCR assay detects the transcript from as little as 50 pg of total RNA . ^^^ RT PCR for PML / RAR alpha mRNA provides a more sensitive test for the t ( 15 ; 17 ) than routine cytogenetics or Northern analysis . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Occurrence of distinct PML RAR alpha fusion gene isoforms in patients with acute promyelocytic leukemia detected by reverse transcriptase / polymerase chain reaction . ^^^ A specific ' nested ' reverse transcriptase / polymerase chain reaction ( RT / PCR ) procedure was used to characterize the expression patterns of PML RAR alpha chimeric mRNAs in 32 patients with acute promyelocytic leukemia ( APL ) . ^^^ The sensitivity of the technique was such that the fusion gene transcript could be detected from as little as 2 . 5 pg of total leukemic cell RNA against a background of 1 microgram of cellular RNA lacking the PML RAR alpha fusion gene transcript ( s ) . ^^^ In 19 cases the PML RAR alpha isoform referred to here as long was identified . ^^^ A third PML RAR alpha mRNA isoform , in which the most 3 ' PML exon present in the long type isoform was truncated in its sequences lying immediately upstream of RAR alpha B region , was found and characterized in a single patient . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The chromosomal rearrangement juxtaposes the retinoic acid receptor alpha ( RAR alpha ) and PML genes , resulting in PML / RAR alpha fusion transcripts . ^^^ Our previous studies have shown that a polymerase chain reaction ( PCR ) amplification product could be obtained from the cDNA of the NB 4 promyelocytic cell line from which the chimaeric PML / RAR alpha was cloned . ^^^ The consistent identification by RT PCR of the fusion of the PML and RAR alpha genes in AML 3 patients suggest that this method will provide a useful tool for the diagnosis and detection of minimal residual disease in these patients . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
RAR alpha gene was proved to translocated from chromosome 17 to a locus PML on chromosome 15 . ^^^ This new chimeric gene , PML RAR alpha is extremely important to understand the leukemogenesis of APL . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Northern blot analyses show that the chimeric fusion transcript PML RAR alpha and the normal allelic PML and RAR alpha transcripts are similarly expressed in both cell lines . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Diagnosis of acute promyelocytic leukaemia by RT PCR : detection of PML RARA and RARA PML fusion transcripts . ^^^ Acute promyelocytic leukaemia ( APL ; AML M 3 ) is identified by a unique t ( 15 ; 17 ) translocation which fuses the PML gene to the retinoic acid receptor alpha gene ( RARA ) . ^^^ Reverse transcription coupled with the polymerase chain reaction ( RT PCR ) has been used to develop a diagnostic test for APL based on the PML RARA fusion message . ^^^ Separate PCR assays were designed to amplify either PML RARA ( 15q+ derived ) or RARA PML ( 17q derived ) chimaeric transcripts . ^^^ PML RARA transcripts were detected in every case from a series of 18 APL patients with cytogenetically confirmed t ( 15 ; 17 ) translocations , whereas RARA PML messages were detected in only 67 % ( 12 / 18 ) of these patients . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Chromosomal translocation t ( 15 ; 17 ) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor , PML . ^^^ A unique mRNA produced in leukemic cells from a t ( 15 ; 17 ) acute promyelocytic leukemia ( APL ) patient encodes a fusion protein between the retinoic acid receptor alpha ( RAR alpha ) and a myeloid gene product called PML . ^^^ The aberrant PML RAR fusion product , while typically retinoic acid responsive , displays both cell type and promoter specific differences from the wild type RAR alpha . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
We have previously shown that the t ( 15 ; 17 ) translocation specifically associated with acute promyelocytic leukemia ( APL ) fuses the retinoic acid receptor alpha ( RAR alpha ) locus to an as yet unknown gene , initially called myl and now renamed PML . ^^^ The PML RAR alpha fusion mRNA generated by the t ( 15 ; 17 ) translocation in acute promyelocytic leukemia encodes a functionally altered RAR . ^^^ The PML RAR alpha mRNA encodes a predicted 106 kd chimeric protein containing most of the PML sequences fused to a large part of RAR alpha , including its DNA and hormone binding domains . ^^^ Identical PML RAR alpha fusion points are found in several patients . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Analysis of the t ( 15 ; 17 ) breaking point revealed that ( 1 ) either RAR alpha on chromosome 17 or the gene named myl on chromosome 15 is abnormal in APL cells , and ( 2 ) the abnormal fused protein myl / RAR alpha is expressed , which is suspected to cause the APL . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelotic leukemia is characterized by a t ( 15 ; 17 ) chromosomal translocation which results in fusion products between PML ( chromosome 15 ) and RAR alpha ( chromosome 17 ) . ^^^ We then discuss the functional properties of PML and show that PMLRAR can interfere with both PML and RAR alpha functions . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Structure and origin of the acute promyelocytic leukemia myl / RAR alpha cDNA and characterization of its retinoid binding and transactivation properties . ^^^ Cloning experiments have established that the chromosome 17 breakpoint maps to the RAR alpha and the 15 to the myl locus . ^^^ The resulting chimeric gene is transcribed as a myl / RAR alpha fusion mRNA . ^^^ By isolating both normal myl and APL myl / RAR alpha cDNAs , we showed that the myl / RAR alpha mRNA encodes for a putative fusion protein with a molecular weight of about 103 kDa , which is made up of 530 amino acids derived from the myl N terminus and 402 amino acids originating from the RAR alpha C terminus . ^^^ The myl / RAR alpha protein acted as a retinoid inducible transcription factor with both ligand independent repressor and ligand dependent activator functions in transactivation experiments of a retinoic acid responsive gene . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The translocation t ( 15 ; 17 ) associated with acute promyelocytic leukemia results in the fusion of the retinoic acid receptor alpha ( RARA ) gene to the PML gene . ^^^ Although leukemic cells with translocations characteristically express only one fusion product , both PML / RARA ( on the 15q+ derivative chromosome ) and RARA / PML ( on the 17q derivative ) are transcribed . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The translocation breakpoints have recently been identified and shown to involve the RAR alpha gene on 17 and myl on 15 . ^^^ Here we report Southern blotting analysis of 26 APLs , including cases with normal karyotypes and atypical morphology , which showed RAR alpha rearrangements in 92 % cases , myl rearrangements in 73 % , and either RAR alpha or myl rearrangements in 100 % . ^^^ Therefore , the RAR alpha and myl rearrangements provide molecular markers for accurately diagnosing APLs and monitoring the course of the disease during and after chemotherapy . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
We report here that , in one APL derived cell line , the RAR alpha gene has been translocated to a locus , myl , on chromosome 15 , resulting in the synthesis of a myl / RAR alpha fusion messenger RNA . ^^^ Using two probes located on either side of the cloned breakpoint , we have found genomic rearrangements of one or other locus in six patients out of eight , demonstrating that the RAR alpha and / or myl genes are frequently rearranged in APL and the breakpoints are clustered . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Secondly , the 15 ; 17 chromosomal translocation specific for APL leads at the molecular genetic level to a chimeric gene fusing the PML and RAR alpha genes and appears to be an instrumental , if not actually the causative event , in the neoplastic process . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
RARA and PML gene rearrangements in acute promyelocytic leukemia with complex translocations and atypical features . ^^^ The translocation t ( 15 ; 17 ) associated with acute promyelocytic leukemia ( APL ) results in fusion of the retinoic acid receptor alpha ( RARA ) gene on chromosome 17 with the putative transcription factor gene , PML , on chromosome 15 . ^^^ A third patient developed a complex karyotype at the time of third relapse , but with no change in RARA and PML gene rearrangement pattern . ^^^ The localization of breakpoints to the second intron of the RARA gene in cytogenetically and phenotypically atypical cases provides additional support for a requisite role of the PML / RARA fusion gene in the pathogenesis of APL . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
A rearrangement between the PML and RAR alpha genes underlies the acute promyelocytic leukemia ( APL ) specific t ( 15 ; 17 ) translocation , leading to the production of a chimeric mRNA . ^^^ Recent development of a reverse transcription polymerase chain reaction ( RT PCR ) assay for the PML / RAR alpha hybrid has proven useful for rapid diagnosis and monitoring of minimal residual disease ( MRD ) in APL patients . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APL ) is characterized by a t ( 15 ; 17 ) chromosomal translocation with breakpoints within the retinoic acid alpha receptor ( RAR alpha ) gene on 17 and the PML gene , which encodes a putative transcription factor , on 15 . ^^^ A PML RAR alpha fusion protein is formed as a consequence of the translocation . ^^^ We show here that expression of the PML RAR alpha protein in K 562 erythroleukemia cells results in a reduced expression of erythroid differentiation markers and a reduced sensitivity to the erythroid differentiative action of heme . ^^^ Overexpression of RAR alpha , but not of PML , elicited a similar inhibition of K 562 erythroid differentiation . ^^^ These findings indicate that overexpression of either RAR alpha or PML / RAR alpha interferes with erythroid differentiation and support the hypothesis that RAR alpha is involved in the regulation of normal hematopoiesis and alteration of the RAR alpha signaling by PML / RAR alpha is implicated in the promyelocytic leukemogenesis . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Analysis of the joining sequences of the t ( 15 ; 17 ) translocation in human acute promyelocytic leukemia : sequence non specific recombination between the PML and RARA genes within identical short stretches . ^^^ Molecular analysis of the t ( 15 ; 17 ) translocation in 70 patients with acute promyelocytic leukemia ( APL ) confirmed that the breakpoints of chromosome 15 were located in two regions of the promyelocytic leukemia ( PML ) gene , mainly introns 3 and 6 , whereas the breakpoints of chromosome 17 were consistently in intron 2 of the retinoic acid receptor alpha ( RARA ) gene . ^^^ There were identical stretches of one to seven nucleotides between the PML and RARA genes in the majority of the joining sequences . ^^^ Furthermore , APL develops only when the PML and RARA genes are rearranged , within restricted genomic regions and a functional PML RARA chimeric product is produced , and this might lead to a clustering of the breakpoints . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
PML gene fuses with the retinoic acid receptor alpha ( RAR alpha ) gene during the t ( 15 ; 17 ) chromosomal translocation of acute promyelocytic leukemia ( APL ) . ^^^ The epitope recognized by PG M 3 is species specific and fixative resistant and is shared by most PML isoforms and PML / RAR alpha fusion proteins . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The primary cytogenetic abnormality in acute promyelocytic leukemia ( APL ; FAB M 3 ) is a reciprocal translocation , t ( 15 ; 17 ) ( q 22 ; q 12 ) , which serves to fuse the PML gene on chromosome 15 to the retinoic acid receptor alpha ( RARA ) gene on chromosome 17 . ^^^ A PML RARA fusion message transcribed from the der ( 15 ) is thought to mediate leukemogenesis . ^^^ Here we report on a combined analysis by molecular genetics and in situ hybridization of these two patients , in which we wanted to determine whether the PML gene has alternative fusion partners or whether cryptic rearrangement of the RARA locus has occurred instead . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
A defect in PML expression is observed in acute promyelocytic leukaemia as a consequence of a chromosomal translocation involving the genes encoding PML and the alpha retinoic acid receptor ( RAR alpha ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The PML gene located on chromosome band 15q22 is involved with the RAR alpha locus ( 17q21 ) in a balanced reciprocal translocation uniquely observed in acute promyelocytic leukemia . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Rapid diagnosis of acute promyelocytic leukemia by immunohistochemical localization of PML / RAR alpha protein . ^^^ Acute promyelocytic leukemia ( APL ) is characterized by a consistent chromosomal aberration that fuses the retinoic acid receptor alpha ( RAR alpha ) gene with the novel gene PML , resulting in the expression of a PML / RAR alpha fusion protein . ^^^ Immunohistochemical examination of APL cells shows a unique abnormal distribution of anti PML and anti RAR alpha antibody labeling . ^^^ IH results agreed with reverse transcription polymerase chain reaction for PML / RAR alpha in 31 of 32 patients with acute myelogenous leukemia , including 5 of 5 patients in whom the initial clinical diagnosis of APL was not supported by cytogenetics , molecular tests , or response to all trans retinoic acid ( RA ) . ^^^ The relative ease and speed of detecting the APL specific PML labeling pattern should make IH a useful diagnostic tool to guide specific therapy of APL , and establish a direct assay for PML / RAR alpha protein expression and localization in individual patient cells . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The PML / RAR alpha fusion gene in the diagnosis and monitoring of acute promyelocytic leukemia . ^^^ The acute promyelocytic leukemia ( APL ) specific t ( 15 ; 17 ) chromosome abnormality is characterized at the molecular level by rearrangement of the PML and RAR alpha genes , resulting in fusion PML / RAR alpha mRNA and a chimeric protein . ^^^ Several studies have highlighted the clinical relevance of PML / RAR alpha detection , which provides a specific diagnosis , prognostic information , and prediction of relapse when monitoring residual disease during the follow up . ^^^ Rare cases of patients with a morphological diagnosis of FAB M 3 AML who lack the specific PML / RAR alpha abnormality have been reported as being unresponsive to differentiation treatment . ^^^ Thus , RT PCR of the hybrid PML / RAR alpha gene is currently performed prospectively as part of cooperative clinical trials aimed at better addressing post remission treatment in APL . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Forty five cases showed chromosomal translocation t ( 15 ; 17 ) and PML / RAR alpha fusion gene ( PML + RAR alpha + APL ) . ^^^ They had typical morphologic change , in which hypergranular cells appeared more frequently in L type of PML / RAR alpha and microgranular cells in S type of PML / RAR alpha . ^^^ Among the 45 PML + RAR alpha + APL patients 8 died early and 37 had complete remission with ATRA . ^^^ In the remainging 5 patients , three had typical APL morphologic features in cytology , but one of them displayed t ( 11 ; 17 ) with PLZF+RARA alpha + , the second showed RAR alpha + PML ( PML RAR alpha + APL ) and the third PML RAR alpha ( PML RAR alpha APL ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
In the t ( 15 ; 17 ) translocation of acute promyelocytic leukemia ( APL ) at least three regions of the PML gene are involved in the reciprocal translocation between the PML and the RAR alpha loci . ^^^ The chimeric PML / RAR alpha fusion transcripts can be demonstrated in all cases of APL , by a specific reverse transcription PCR ( RT PCR ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Although the mechanism of its effectiveness upon APL remains unclear , the PML retinoic acid receptor alpha ( RARA ) chimeric protein produced by t ( 15 ; 17 ) is assumed to underlie the sensitivity of APL cells to ATRA . ^^^ There are two major isoforms of PML RARA transcripts ; short ( S ) and long ( L ) , according to the breakpoints in the PML gene . ^^^ These data indicated that isoforms of PML RARA fused transcripts affect neither the clinical features of APL nor the prognosis after treatment with ATRA . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The t ( 15 ; 17 ) chromosomal translocation , specific for acute promyelocytic leukemia ( APL ) , fuses the PML gene to the retinoic acid receptor alpha ( RAR alpha ) gene , resulting in expression of a PML RAR alpha hybrid protein . ^^^ In this report , we analyzed the nature of PML RAR alpha containing complexes in nuclear protein extracts of t ( 15 ; 17 ) positive cells . ^^^ We show that endogenous PML RAR alpha can bind to DNA as a homodimer , in contrast to RAR alpha that requires the retinoid 10 receptor ( RXR ) dimerization partner . ^^^ In addition , these cells contain oligomeric complexes of PML RAR alpha and endogenous RXR . ^^^ Treatment with retinoic acid results in a decrease of PML RAR alpha protein levels and , as a consequence , of DNA binding by the different complexes . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Reverse transcribed polymerase chain reaction assay confirmed the initial diagnosis of PML by amplification of the PML specific PML / RAR alpha fusion transcript . ^^^ Conclusion : This case report confirms that a characteristic translocation t ( 15 ; 17 ) is not always detectable in PML blasts by karyotype analysis despite presence of specific PML / RAR alpha transcripts . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Rearrangements of the RARA and PML genes in a cytogenetic variant of acute promyelocytic leukemia . ^^^ Acute promyelocytic leukemia ( APL ) is usually associated with the translocation t ( 15 ; 17 ) ( q 22 ; q 12 21 ) , which disrupts the retinoic acid receptor alpha ( RARA ) gene on chromosome 17 and the PML gene on chromosome 15 . ^^^ Molecular analysis showed RARA and PML rearrangements , suggesting that the chromosome abnormality corresponded to a variant translocation . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Breakpoint clusters of the PML gene in acute promyelocytic leukemia : primary structure of the reciprocal products of the PML RARA gene in a patient with t ( 15 ; 17 ) . ^^^ DNA studies of the translocation t ( 15 ; 17 ) in acute promyelocytic leukemia ( APL ) have shown that the retinoic acid receptor alpha ( RARA ) gene on chromosome 17 is juxtaposed to the promyelocytic leukemia ( PML ) gene on chromosome 15 . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The specific chromosomal translocation t ( 15 ; 17 ) in APL has been shown to fuse the gene for the retinoic acid receptor alpha ( RAR alpha ) with a chromosome 15q locus , PML . ^^^ Alterations to the RAR alpha and the PML gene structures in the t ( 15 ; 17 ) have been characterized and used as specific molecular marker for diagnosis of the disease . ^^^ PML / RAR alpha antagonizes wild type PML and RXR and could block the differentiation pathways mediated by these two regulators . ^^^ Both PML / RAR alpha and PLZF / RAR alpha display the `` dominant negative ' ' effect on the wild type RAR / RXR . ^^^ Morphologically defined APL cases which however do not have PML / RAR alpha generally show no response to ATRA . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The purpose of this work was to assess the re arrangement of RAR alpha and pml genes in a group of patients with acute promyelocytic leukaemia ( APL ) in different stages of the disease . ^^^ The molecular study of RAR alpha and pml genes was made with the Southern method . ^^^ These results are in concordance with previous studies , in which re arrangement of RAR alpha and pml genes had been found in APL , despite there are instances in which no cytogenetic anomalies are found ; this confirms the interest of molecular studies in the diagnosis and follow up of APL patients . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The chromosomal translocation t ( 15 ; 17 ) ( q 22 ; q 12 ) is a consistent feature of acute promyelocytic leukemia ( APL ) that results in the disruption of genes for the zinc finger transcription factor PML and the retinoic acid receptor alpha ( RAR alpha ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The PML and retinoic acid receptor alpha ( RAR alpha ) transcription factor genes are involved at translocation breakpoint . ^^^ This antibody was able to detect a 90 kD PML protein and a 110 kD PML RAR alpha fusion protein by Western blotting and a nuclear speckled pattern in all cell lines by immunofluorescent staining . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Growth suppression of acute promyelocytic leukemia cells having increased expression of the non rearranged alleles : RAR alpha or PML . ^^^ The balanced t ( 15 ; 17 ) rearrangement found in acute promyelocytic leukemia ( APL ) cells fuses PML on chromosome 15 to the retinoic acid receptor alpha ( RAR alpha ) on chromosome 17 . ^^^ PML / RAR alpha is expressed in APL cells with the non rearranged alleles , PML and RAR alpha . ^^^ The roles of PML and RAR alpha in the RA response of APL have not yet been fully explored . ^^^ This study examines these roles by individually transfecting RAR alpha and PML into NB 4 APL cells . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
A rearrangement between the PML and RAR alpha genes underlies the acute promyelocytic leukemia ( APL ) specific t ( 15 ; 17 ) translocation , leading to the production of a chimeric mRNA . ^^^ Recent development of a reverse transcription polymerase chain reaction ( RT PCR ) assay for the PML / RAR alpha hybrid has proven useful for rapid diagnosis and monitoring of minimal residual disease ( MRD ) in APL patients . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
APL is characterized cytogenetically by a t ( 15 ; 17 ) translocation which involves both the PML gene on chromosome 15 and the RARa gene on chromosome 17 and gives rise to the PML / RARa fusion protein . ^^^ The high sensitivity of the promyelocytic blasts to all trans RA should be related to the presence in APL blast of an abnormal protein , the PML / RAR alpha . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Patients with acute promyelocytic leukemia ( APL ) associated with the t ( 15 ; 17 ) translocation and fusion of the promyelocytic leukemia ( PML ) and retinoic acid receptor alpha ( RAR alpha ) genes achieve complete remission but not cure with all trans retinoic acid ( RA ) , NB 4 , a cell line derived from a patient with t ( 15 ; 17 ) APL that undergoes granulocytic differentiation when treated with pharmacologic doses of RA , was used as a model for differentiation therapy of APL . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
As a result , a portion of the RAR alpha gene becomes fused with a chromosome 15 locus termed PML ( promyelocytic myeloid leukemia ) from which chimeric PML / RAR alpha fusion mRNAs are expressed . ^^^ The presence of these fusion transcripts in APL patients strongly support the hypothesis that both the t ( 15 ; 17 ) , and thus PML / RAR alpha , play a crucial role in the leukemogenesis of this disease . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The translocation fuses the PML gene to the retinoic acid receptor alpha ( RAR alpha ) gene resulting in the production of a PML RAR alpha fusion protein . ^^^ The hybrid molecule retains most of the functional domains of both native products , PML and RAR alpha , but it has novel features . ^^^ PML RAR alpha also acquires novel transcriptional properties if compared to RAR alpha , it does so either by direct binding to target gene regulatory sequences or by protein interaction with cofactors . ^^^ Expression of PML RAR alpha in HL 60 or U 937 cell has been shown to block their maturation while it can force their differentiation at high doses of retinoic acid . ^^^ Different mechanisms are proposed to explain how PML RAR alpha blocks differentiation and how this may be reversed by retinoic acid . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The nonrandom chromosomal translocation t ( 15 ; 17 ) ( q 22 ; q 21 ) in acute promyelocytic leukemia ( APL ) juxtaposes the genes for retinoic acid receptor alpha ( RAR alpha ) and the putative zinc finger transcription factor PML . ^^^ The breakpoint site encodes fusion protein PML RAR alpha , which is able to form a heterodimer with PML . ^^^ It was hypothesized that PML RAR alpha is a dominant negative inhibitor of PML . ^^^ Our results demonstrated that PML , but not PML RAR alpha , is a growth suppressor . ^^^ Cotransfection of PML with PML RAR alpha resulted in a significant reduction in PML ' s transformation suppressor function in vivo , indicating that the fusion protein can be a dominant negative inhibitor of PML function in APL cells . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Efficacy of fluorescence in situ hybridization for detecting PML / RARA gene fusion in treated and untreated acute promyelocytic leukemia . ^^^ OBJECTIVE : To test the efficacy of fluorescence in situ hybridization ( FISH ) for detection of fusion of the promyelocytic leukemia ( PML ) and retinoic acid receptor alpha ( RARA ) genes in patients with treated or untreated acute promyelocytic leukemia ( APL ) . ^^^ PML / RARA fusion was detectable in three patients with hypogranular APL and in three with a cytogenetic variant of the t ( 15 ; 17 ) . ^^^ CONCLUSION : The results of this study suggest that FISH with PML and RARA probes can be used to diagnose APL and may be useful for monitoring treated patients . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
This observation justifies the use of chemotherapy for at least 3 years after CR induced by ATRA . ( 5 ) It seems likely that the fusion gene PML RARA plays an important role in APL leukemogenesis and in its response to the ATRA treatment . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Translocation of the RAR alpha locus to the PML or PLZF gene in acute promyelocytic leukaemia . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APML ) almost always involves a chromosomal translocation t ( 15 : 17 ) that results in the fusion of the retinoic acid receptor alpha ( RAR alpha ) gene with a transcription factor gene called PML . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Human CD 4 lymphocytes specifically recognize a peptide representing the fusion region of the hybrid protein pml / RAR alpha present in acute promyelocytic leukemia cells . ^^^ We tested whether a peptide ( BCR1 / 25 ) encompassing the fusion region of the hybrid molecule pml / RAR alpha , which is selectively expressed by acute promyelocytic leukemia ( APL ) cells , can be recognized by human T lymphocytes in vitro . ^^^ Control peptides corresponding to the normal pml and RAR alpha proteins were not recognized . ^^^ The autologous DE LCL containing a transduced pml / RAR alpha fusion gene and expressing a bcr 1 type of the pml / RAR alpha hybrid protein induced the proliferation of DE anti BCR1 / 25 T cell clones . ^^^ It is concluded that the bcr 1 type pml / RAR alpha fusion protein of APL contains an antigenic site , absent from the normal parent molecules and recognized by human CD4+ lymphocytes . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The chromosomal translocation t ( 15 ; 17 ) ( q 22 : 21 ) of acute promyelocytic leukemia ( APL ) fuses PML , a novel gene , with RAR alpha , a retinoic acid receptor gene . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
PML and RAR alpha gene rearrangements were observed in the two cases where molecular analysis was performed . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
A ribozyme which discriminates in vitro between PML / RAR alpha , the t ( 15 ; 17 ) associated fusion RNA of acute promyelocytic leukemia , and PML and RAR alpha , the transcripts from the nonrearranged alleles . ^^^ Acute promyelocytic leukemia is associated with a chromosomal translocation which results in the fusion of genes encoding a putative transcription factor ( PML ) and the retinoic acid receptor alpha ( RAR alpha ) . ^^^ It is suggested that the PML / RAR alpha fusion protein functions as an inhibitor of myeloid differentiation . ^^^ Hammerhead ribozymes , which by hybridizing to both PML and RAR alpha sequences discriminate between the fusion transcript and the normal transcripts from the nonrearranged alleles , were designed and synthesized . ^^^ Using a full length PML / RAR alpha RNA or an RNA corresponding to 788 nucleotides of the PML / RAR alpha mRNA and a full length RAR alpha RNA or an RNA corresponding to 960 nucleotides of the RAR alpha mRNA as model substrates , the catalytic behavior of several ribozymes was studied . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The characteristic balanced 15 ; 17 translocation , t ( 15 ; 17 ) , of acute promyelocytic leukemia ( APL ) fuses the retinoic acid receptor alpha ( RAR alpha ) gene on chromosome 17 to PML , a recently described gene of unknown function , on chromosome 15 . ^^^ PML / RAR alpha fusion mRNA ' s can be detected by a reverse transcription polymerase chain reaction ( RT PCR ) assay . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Effect of the acute promyelocytic leukemia PML / RAR alpha protein on differentiation and survival of myeloid precursors . ^^^ Acute promyelocytic leukaemia is also characterized by a 15 ; 17 chromosome translocation ( 5 ) with breakpoints within the retinoic acid alpha receptor ( RAR alpha ) gene on 17 and within the PML gene , that encodes a putative transcription factor of unknown function ( 6 7 ) , on 15 ( 8 10 ) . ^^^ As a consequence of the translocation a PML / RAR alpha gene is formed . ^^^ It is transcriptionally active and encodes a PML / RAR alpha fusion protein detectable in all APL cases ( 11 14 ) . ^^^ We expressed the PML / RAR alpha protein in U 937 myeloid precursor cell line and show that they : 1 ) lose the capacity to differentiate under the action of different stimuli ( vitamin D 3 , transforming growth factor beta 1 ) ; 2 ) acquire enhanced sensitivity to retinoic acid ; 3 ) exhibit a higher growth rate that is due to a reduction in apoptotic cell death . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Molecular studies of chromosomal translocation ( 15 ; 17 ) in acute promyelocytic leukemia ( APL ) have shown that retinoic acid receptor A ( RARA ) gene on chromosome 17 is juxtaposed to the PML gene on chromosome 15 . ^^^ This results in a PML RARA chimeric gene . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Molecular analysis of the APL breakpoint has revealed the involvement of the retinoic acid receptor alpha ( RARA ) gene on chromosome 17 and the promyelocytic leukaemia ( PML ) gene on chromosome 15 . ^^^ Both reciprocal fusion products which arise as a result of the translocation , PML / RAR alpha and RAR alpha / PML , are expressed in many patients . ^^^ PML / RAR alpha , is implicated in leukaemogenesis , and may block myeloid differentiation directly and / or interfere with the normal function ( s ) of PML and / or RAR alpha . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
This translocation juxta poses the promyelocytic leukemia ( PML ) gene on chromosome 15 and the retinoic acid receptor alpha ( RARA ) gene on chromosome 17 , resulting in the formation of a chimeric mRNA transcript . ^^^ We describe a patient with the microgranular variant form of APL , with no detectable cytogenetic abnormality of either chromosomes 15 or 17 , who nevertheless had juxtaposition of PML and RARA genes and expressed a chimeric transcript . ^^^ Nevertheless , FISH using cosmid probes for PML and RARA showed their juxtaposition on one chromosome 15 homolog . ^^^ DNA analysis by Southern blotting , performed with a variety of probes including PML , RARA and retinoic acid receptor beta ( RARB ) , showed a rearrangement in PML . ^^^ Reverse transcriptase polymerase chain reaction ( RT PCR ) confirmed the existence of hybrid transcripts of 276 , 455 bp and 623 bp , from PML RARA on the der ( 15 ) chromosome , consistent with alternate exon splicing of the long form of the transcript occurring in 50 % to 60 % of patients with APL . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APL ) has been characterized by 15 ; 17 chromosomal translocation , which involves the retinoic acid receptor alpha ( RARA ) gene on chromosome 17 and the PML gene on chromosome 15 . ^^^ The breakpoints have been mapped to three cluster regions in the PML gene , and to RARA gene intron 2 . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
This translocation involves the retinoic acid receptor alpha ( RAR alpha ) on chromosome 17 and the promyelocytic leukemia locus ( PML ) on chromosome 15 and results in the transcription of novel fusion messenger RNAs . ^^^ In 24 of 26 samples , rearrangements of the PML and RAR alpha , loci could be detected by Southern blotting after digestion with MluI and BssHII . ^^^ Furthermore , co migration of the rearranged fragments , detected by hybridization to probes for the PML and RAR alpha genes , demonstrated that these loci were juxtaposed . ^^^ The diagnostic accuracy was compared to cytogenetics and the reverse transcriptase polymerase chain reaction for the novel PML RAR alpha fusion transcript . ^^^ In contrast to conventional electrophoresis based on rearrangement of RAR alpha , the ability to demonstrate directly co migration of the PML and RAR alpha loci enables this method to distinguish the t ( 15 ; 17 ) translocation from variant translocations such as the t ( 11 ; 15 ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
It has been shown that the retinoic acid receptor alpha ( RARA ) gene , normally located on chromosome 17 , was fused with a new transcription unit PML , normally localized on chromosome 15 . ^^^ These two types of rearrangement constitute the basis for the heterogeneity of the PML RARA fusion gene and its possible biological significance remains to be explored . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
It has become clear that the PML / RAR alpha fusion protein is expressed in most cases of APL , and this protein presumably contributes to leukaemia initiation and / or progression . ^^^ PML / RAR alpha appears to specifically block the further differentiation of myeloid progenitor cells , although the mechanism of its action is not known . ^^^ However , the possibility remains that PML / RAR alpha may have a novel function . ^^^ These include whether PML is a transcription factor ; the identification of its target genes and response elements , and the role of PML / RAR alpha and RA in their regulation . ^^^ Also whether the expression of PML / RAR alpha in bone marrow cells ( either by itself or in combination with other oncogenes ) alters their tumourigenicity or differentiation potential . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The PML RAR alpha gene product of the t ( 15 ; 17 ) translocation inhibits retinoic acid induced granulocytic differentiation and mediated transactivation in human myeloid cells . ^^^ Acute promyelocytic leukemia ( APL ) is characterized by an arrest of granulocytic differentiation and a reciprocal t ( 15 ; 17 ) translocation fusing the PML gene to the retinoic acid receptor alpha ( RAR alpha ) gene . ^^^ In non hematopoietic cells , the transfected PML RAR alpha product binds all trans retinoic acid and exhibits altered transactivating properties when compared with RAR alpha . ^^^ A major question raised by these observations is whether PML RAR alpha contributes to the inhibition of myeloid differentiation . ^^^ We find that in myeloid cell lines responsive to retinoic acid , PML RAR alpha blocks retinoic acid mediated transactivation and totally abrogates the retinoic acid mediated granulocytic differentiation . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Retinoic acid regulates aberrant nuclear localization of PML RAR alpha in acute promyelocytic leukemia cells . ^^^ Acute promyelocytic leukemia ( APL ) is characterized by a specific t ( 15 ; 17 ) translocation that fuses the retinoic acid receptor alpha ( RAR alpha ) to a novel gene product , PML . ^^^ In APL cells , the PML RAR alpha hybrid displays an abnormal localization and directs RXR and other nuclear antigens into aberrant structures that are tightly bound to chromatin . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Chromosome translocation t ( 15 ; 17 ) , the breakpoints of which are in the PML gene on chromosome 15 and retinoic acid receptor alpha ( RAR alpha ) gene on chromosome 17 , is specifically found in acute promyelocytic leukemia ( APL ) . ^^^ Clinically typical APL without t ( 15 ; 17 ) and with the PML RAR alpha fusion transcripts or rearrangements in PML and / or RAR alpha gene has been reported , suggesting submicroscopic changes at the molecular level without apparent t ( 15 ; 17 ) or observation of normal metaphases . ^^^ PML RAR alpha fusion transcript was detected in an APL case with trisomy 8 but without t ( 15 ; 17 ) , indicating that the leukemic cells lacked t ( 15 ; 17 ) and still expressed the PML RAR alpha fusion transcripts . ^^^ This indicates that the same submicroscopic molecular changes as in APL with t ( 15 ; 17 ) do occur in APL without t ( 15 ; 17 ) and supports the use of molecular analysis for PML RAR alpha fusion in APL . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
At diagnosis , 13 pts had promyelocytic leukemia ( PML ) retinoic acid receptor alpha ( RAR alpha ) rearranged acute promyelocytic leukemia ( APL ) , 8 Philadelphia positive ( Ph ' + ) break point cluster region ( BCR+ ) chronic myeloid leukemia ( CML ) , and 3 Ph ' + ( BCR+ ) acute lymphoblastic leukemia ( ALL ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Localization of the chromosome 15 breakpoints and expression of multiple PML RAR alpha transcripts in acute promyelocytic leukemia : a study of 28 Chinese patients . ^^^ Translocation ( 15 ; 17 ) ( q 22 ; q 12 q21 ) is a chromosome aberration specifically found in acute promyelocytic leukemia ( APL ) , that generates a chimeric gene between the promyelocytic leukemia ( PML ) gene on chromosome 15 and the retinoic acid receptor alpha ( RARA ) gene , on chromosome 17 . ^^^ In the course of molecular investigations of a series of 28 Chinese patients with APL , we have simultaneously used Southern blot and reverse transcriptase polymerase chain reaction ( RT PCR ) analysis to characterize the PML gene breakpoints on chromosome 15 and identify PML RARA fusion transcripts . ^^^ In addition , structural data provided by PML RARA transcripts allowed us to more accurately locate the 3 ' borders of clusters bcr 1 and bcr 3 . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Breakpoints of the 15 ; 17 translocation in patients with acute promyelocytic leukemia ( APL ) have been identified within PML and retinoic acid receptor a ( RARA ) genes in chromosomes 15 and 17 , respectively . ^^^ A wide heterogeneity was observed in the breakpoints on the PML and RARA genes . ^^^ In this study , PCR analysis using genomic DNA of APL cells is proved to be useful for identifying the breakpoints of the PML and the RARA genes . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The acute promyelocytic leukemia specific PML RAR alpha fusion protein inhibits differentiation and promotes survival of myeloid precursor cells . ^^^ Acute promyelocytic leukemia is characterized by a 15 ; 17 chromosome translocation with breakpoints within the retinoic acid alpha receptor ( RAR alpha ) gene on 17 and the PML gene , which encodes a putative transcription factor , on 15 . ^^^ A PML RAR alpha fusion protein is formed as a consequence of the translocation . ^^^ We expressed the PML RAR alpha protein in U 937 myeloid precursor cells and showed that they lost the capacity to differentiate under the action of different stimuli ( vitamin D 3 and transforming growth factor beta 1 ) , acquired enhanced sensitivity to retinoic acid , and exhibited a higher growth rate consequent to diminished apoptotic cell death . ^^^ These results provide evidence of biological activity of PML RAR alpha and recapitulate critical features of the promyelocytic leukemia phenotype . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Molecular study on the distinct isoforms of PML RAR alpha fusion gene transcripts in acute promyelocytic leukemia ] . ^^^ The chromosomal translocation t ( 15 ; 17 ) in acute promyelocytic leukemia ( APL ) results in the production of a fusion gene PML RAR alpha specific for the disease . ^^^ Using the retrotranscriptase / polymerase chain reaction ( RT / PCR ) , we cloned several distinct isoforms of PML RAR alpha fusion transcripts and obtained their nucleic acid sequences . ^^^ The results showed that the RAR alpha derived sequences were the same in fusion genes while the PML sequences differed as a result of the locations of PML gene breakpoints . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Reverse transcription polymerase chain reaction for PML RAR alpha fusion transcripts in acute promyelocytic leukemia and its application to minimal residual leukemia detection . ^^^ Chromosome translocation t ( 15 ; 17 ) specifically found in acute promyelocytic leukemia ( APL ) results in cleavage in the introns of PML gene on chromosome 15 and in the intron of the retinoic acid receptor alpha ( RAR alpha ) gene on chromosome 17 , creation and expression of PML RAR alpha and RAR alpha PML fusion genes . ^^^ Reverse transcription polymerase chain reaction ( RT PCR ) was applied to detect the PML RAR alpha fusion transcripts rapidly in APL patients . ^^^ This method was applied to detect minimal residual leukemia cells in an APL patient who had undergone allogeneic bone marrow transplantation , in whom the RT PCR could not detect the PML RAR alpha fusion transcripts at several post transplant time points . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
We determined the breakpoints of the RAR alpha and PML genes in acute promyelocytic leukemia ( APL ) cells from 40 patients using Southern blot analysis . ^^^ While the breakpoints of the RAR alpha gene were consistently within intron 2 , we found two major clusters in the breakpoints of the PML gene . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Fusion proteins ( named PMLRAR ) between PML and the retinoic acid receptor alpha ( RAR alpha ) are generated as a result of the t ( 15 ; 17 ) chromosomal translocation found in acute promyelocytic leukemia ( APL ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
They are localized on a previously unknown gene , PML , on chromosome 15 and in the gene that encodes the alpha retinoic acid receptor ( RAR alpha ) on 17 . ^^^ The translocation , which is balanced and reciprocal , leads to the formation of two fusion genes , PML / RAR alpha and RAR alpha / PML . ^^^ The PML / RAR alpha gene codes for two abnormal proteins : the PML / RAR alpha fusion protein and an abnormal PML protein , the RAR alpha / PML gene encodes the RAR alpha / PML fusion protein . ^^^ Preliminary results suggest that the PML / RAR alpha fusion protein is responsible for two important properties of the APL phenotype : the differentiation block characteristic of the leukemic blasts and the high sensitivity of the blasts to the differentiative action of retinoic acid ( RA ) both in vivo and in vitro . ^^^ The mechanism through which PML / RAR alpha exerts its biological function remains unknown . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Detection of minimal residual disease in acute promyelocytic leukemia by a reverse transcription polymerase chain reaction assay for the PML / RAR alpha fusion mRNA . ^^^ The characteristic reciprocal translocation t ( 15 ; 17 ) of acute promyelocytic leukemia ( APL ) disrupts the PML gene on chromosome 15 and the retinoic acid receptor alpha ( RAR alpha ) gene on chromosome 17 . ^^^ PML / RAR alpha fusion mRNAs are then transcribed and can be detected by a newly described reverse transcription polymerase chain reaction ( RT PCR ) assay . ^^^ Using RT followed by nested PCR amplification for PML / RAR alpha , we serially evaluated bone marrow aspirates from patients with APL who were treated with all trans retinoic acid ( RA ) for induction , followed by all trans RA as maintenance or cytotoxic drugs as consolidation . ^^^ At diagnosis , PML / RAR alpha mRNA was detected in all patients . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APL ) is thought to be caused by the t ( 15 , 17 ) translocation that fuses the PML gene to that of the retinoic acid receptor alpha ( RAR alpha ) and generates a PML / RAR alpha fusion protein . ^^^ In this report , we have examined the expression of PML and PML / RAR alpha in normal and APL cells . ^^^ By immunofluorescence or immunocytochemistry , we show that PML has a speckled nuclear pattern of expression that contrasts with that of PML / RAR alpha ( mostly a micropunctuated nuclear pattern or a cytoplasmic localization ) . ^^^ The APL derived cell line NB 4 that expresses both the PML and PML / RAR alpha genes also shows the fine micropunctuated nuclear pattern , suggesting a dominant effect of the fusion protein over the localization of wild type PML . ^^^ RA treatment of NB 4 cells or clones expressing PML / RAR alpha gradually leads to a PML pattern before apparent morphologic maturation . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The cytogenetic marker , t ( 15 ; 17 ) , reflects a molecular defect that splices two transcription factors , PML and RARA , to produce chimeric mRNA and proteins . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
In many APL patients , translocation between RAR alpha gene and an oncogenic gene , PML , can be detected , although the roles of their fusion products ( RAR alpha PML and PML RAR alpha ) in APL induction have not been understood . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
It aroused considerable interest well beyond the hematologic field during the last five years since APL has two unique features 1 ) the remission of the disease obtained with all trans retinoic acid ( ATRA ) treatment 2 ) the presence in APL blasts of an abnormal protein , the promyelocytic myeloid leukemia / retinoic acid receptor ( PML / RAR alpha ) protein . ^^^ APL is characterized cytogenetically by a t ( 15 ; 17 ) translocation which involves both the PML gene on chromosome 15 and the RAR alpha gene on chromosome 17 and gives rise to the PML / RAR alpha fusion protein . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Moreover , in the t ( 15 ; 17 ) translocation of acute promyelocytic leukaemia ( APL ) , PML fusion to the retinoic acid receptor alpha ( RAR alpha ) is the likely molecular basis of leukaemogenesis . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
PML , a Ring finger protein , participates in the disruption of normal myeloid differentiation when fused to the retinoic acid receptor alpha ( RAR alpha ) by the translocation between chromosomes ( Chrs ) 15 and 17 in acute promyelocytic leukemia ( APL ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
We report here that the fusion of PML , a nuclear protein defined by the t ( 15 ; 17 ) chromosomal translocation in acute promyelocytic leukemia , with retinoic acid receptor alpha ( RAR alpha ) changes the RAR alpha from a retinoic acid ( RA ) dependent inhibitor to a RA dependent activator of AP 1 transcriptional activity . ^^^ The PML RAR alpha chimera cooperates with c Jun and , strikingly , with c Fos to stimulate the transcription of both synthetic and natural reporter genes containing an AP 1 site . ^^^ Further , in the absence of RA , a circumstance in which RAR alpha has no effect on AP 1 activity , PML RAR alpha is an inhibitor . ^^^ Deletion of the dimerization , transactivation , or DNA binding domains of c Jun and removal of the PML dimerization domain in the PML RAR alpha hybrid abrogates their transcriptional cooperatively . ^^^ In view of the association between AP 1 activity and hemopoietic differentiation , we suggest that these properties of PML RAR alpha could contribute to the leukemic phenotype and its response to RA . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The t ( 15 ; 17 ) translocation , specifically associated with the human acute promyelocytic leukemia ( APL ) , fuses the retinoic acid receptor alpha ( RAR alpha ) to a novel gene PML generating the hybrid protein PML RAR . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APL ) is characterized by the t ( 15 ; 17 ) which involves the PML gene and the retinoic acid receptor alpha ( RAR alpha ) gene , and the subsequent PML / RAR alpha fusion gene is a key event in the leukemogenesis of APL . ^^^ We found that the PML / RAR alpha fusion gene was expressed in both granulocytic / macrophage and erythroid colonies in a few patients with APL . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APL ; M 3 in the FAB classification ) is specifically associated with the t ( 15 ; 17 ) ( q 23 ; q 12 ) and the consequent formation of a PML / RARA fusion gene . ^^^ Molecular studies evidenced RARA rearrangement but showed neither PML rearrangement nor PML / RARA fusion . ^^^ Whereas RARA rearrangement appears sufficient for an APL like phenotype , it seems that the presence of a classical PML / RARA is required for typical APL with response to ATRA . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
PML has been identified through its fusion to the RAR alpha gene in acute promyelocytic leukemia ( APL ) . ^^^ In APL cells , IFNs induced both PML and PML / RAR alpha expression , resulting in an increased sequestration of PML and RXRs in the microspeckles induced by the fusion protein . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The chromosome 17 breakpoint was localized to intron 2 of RARA by Southern blotting , and there was no evidence at the molecular level for rearrangement at PML locus . ^^^ This heterogeneity suggests that the variant fusion partners of RARA in APL encode factors with properties both common to and distinct from those of PML . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
AMP signalling is decisive for recovery of nuclear bodies ( PODs ) during maturation of RA resistant t ( 15 ; 17 ) promyelocytic leukemia NB 4 cells expressing PML RAR alpha . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Accelerated degradation of PML retinoic acid receptor alpha ( PML RARA ) oncoprotein by all trans retinoic acid in acute promyelocytic leukemia : possible role of the proteasome pathway . ^^^ The PML retinoic acid receptor alpha ( RARA ) oncoprotein , which is generated by the translocation , blocks the differentiation , and ATRA is thought to modulate the dominant negative function of PML RARA . ^^^ However , the molecular effect of ATRA on PML RARA is unknown . ^^^ In this study , we showed by means of immunoblotting that the expression of PML RARA decreased within 12 h in APL cells treated with ATRA at concentrations greater than 0 . 1 microM . ^^^ The decrease of PML RARA was associated with restoration of the normal subcellular PML localization . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Complex t ( 1 ; 15 ; 17 ) in acute promyelocytic leukemia with duplication of RAR alpha and PML sequences . ^^^ Fluorescence in situ hybridization ( FISH ) with t ( 15 ; 17 ) , RAR alpha , and 17qter probes and with chromosome 1 , 15 , and 17 paints demonstrated that the der ( 17 ) consisted of a complex rearrangement with duplication of both RAR alpha and PML , insertion of chromosome 1 sequences , and double insertion of chromosome 15 sequences . ^^^ The fusion of RAR alpha and PML consistent with APL appears to have occurred at the distal juxtaposition of these sequences in the derivative chromosome . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Peptide nucleic acids ( PNAs ) complementary to the 15 bases around the fusion point of both genomic DNA and cDNA of the promyelocytic leukemia / retinoic acid receptor alpha ( PML / RAR alpha ; P / R ) hybrid gene present in acute promyelocytic leukemia cells were synthesized and shown by gel retardation experiments to specifically bind oligonucleotides corresponding to the fusion region of the P / R molecule . ^^^ However , this PNA , although able to specifically clamp polymerase chain reaction , was incapable of inhibiting in vitro translation of the PML / RAR alpha mRNA , even when a bis PNA was used . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The PML gene is fused to the retinoic acid receptor alpha ( RAR alpha ) gene in t ( 15 ; 17 ) acute promyelocytic leukemia ( APL ) , creating a PML RAR alpha fusion oncoprotein . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Molecular analysis of the PML / RAR alpha chimeric gene in pediatric acute promyelocytic leukemia . ^^^ To compare molecular events among pediatric and adult APL cases , we designed two sets of oligonucleotide primers using published cDNA sequence for PML / RAR alpha fusion transcripts , and undertook reverse transcriptase polymerase chain reaction ( RT PCR ) analysis of 22 US pediatric cases of APL . ^^^ PML / RAR alpha fusion transcripts were detected in all APL cases , including two cases lacking cytogenetic evidence of t ( 15 ; 17 ) . ^^^ Consistent with previously published data , case analysis demonstrated fusion products resulting from three breakpoint cluster regions ( bcr ) in PML , and a single breakpoint region in intron 2 of RAR alpha . ^^^ RT PCR with these primer sets is a reliable method for detecting PML / RAR alpha chimeric transcript in t ( 15 ; 17 ) containing APL . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
However , we show here that in cultured NB 4 ( ref . 6 ) human acute promyelocytic leukaemia cells treated with either an RAR alpha selective agonist alone , or certain RAR alpha antagonists in combination with an RXR agonist , receptor DNA binding is induced in vivo , resulting in expression of the target genes of retinoic acid as well as acute promyelocytic leukaemia protein ( PML ) relocation to nuclear bodies and differentiation before apoptosis . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APL ) is characterized by a unique hemorrhagic syndrome , disseminated intravascular coagulation , and the association with the specific ( 15 ; 17 chi q 22 23 : q 12 21 ) translocation , which disrupts the retinoic acid receptor alpha ( RARA ) and the promyelocytic leukemia ( PML ) genes . ^^^ The t ( 15 ; 17 ) leads to the formation of two reciprocal fusion genes , PML / RARA on chromosome 15 and RARA / PML on chromosome 17 ; it is responsible for the unique response of the disease to retinoic acid ( ATRA ) treatment . ^^^ Rearrangements of RARA and PML were documented in some of these variant translocations . ^^^ In contrast , recent molecular analysis of APL cases with cytogenetically normal chromosomes 15 and 17 revealed the occurrence of submicroscopic translocations , leading to the formation of non reciprocal fusion genes , either PML / RARA or RARA / PML only . ^^^ Demonstration of the existence , in some APL like leukemias , of masked translocations with involvement of PML and RARA , thus allows to ( 1 ) confirm the diagnosis of APL , ( 2 ) adapt the treatment and ( 3 ) monitor the residual disease . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The PML / RAR alpha oncoprotein is a direct molecular target of retinoic acid in acute promyelocytic leukemia cells . ^^^ Acute promyelocytic leukemia ( APL ) is characterized by the translocation , t ( 15 ; 17 ) and the expression of a PML / RAR alpha fusion protein that is diagnostic of the disease . ^^^ There is evidence that PML / RAR alpha protein acts as a dominant negative inhibitor of normal retinoid receptor function and myeloid differentiation . ^^^ We now show that the PML / RAR alpha fusion product is directly downregulated in response to retinoic acid ( tRA ) treatment in the human APL cell line , NB 4 . tRA treatment induces loss of PML / RAR alpha at the protein level but not at the level of mRNA , as determined by Northern blots , by Western blots , and by ligand binding assays and in binding to RA responsive DNA elements . ^^^ This evidence suggests that tRA induces synthesis of a protein that selectively degrades PML / RAR alpha . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
In the APL cell line NB 4 , the PML gene is fused with the RAR alpha gene due to a chromosomal rearrangement . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukaemia ( APL ) arises following a reciprocal translocation t ( 15 ; 17 ) that fuses PML with retinoic acid receptor alpha ( RARA ) . ^^^ The PML RARA fusion protein targets and disrupts nuclear multiprotein complexes called PODs , ND 10 or NBs , a process which is associated with a block in myeloid differentiation leading to APL . ^^^ There is no significant colocalisation observed between the staining of PML / PML RARA and PIC 1 in an APL derived cell line NB 4 , as compared to cells expressing only wild type PML . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Interferon augments PML and PML / RAR alpha expression in normal myeloid and acute promyelocytic cells and cooperates with all trans retinoic acid to induce maturation of a retinoid resistant promyelocytic cell line . ^^^ The PML gene is fused to the retinoic acid receptor alpha gene ( RAR alpha ) in the acute promyelocytic leukemia ( APL ) 15 ; 17 translocation . ^^^ Similarly , interferons could act on APL cells , alone or in combination with all trans retinoic acid ( RA ) , especially if the PML / RAR alpha fusion transcript that results from the t ( 15 ; 17 ) is induced by interferon . ^^^ We report here that PML is expressed at low levels or not expressed in normal circulating human monocytes , lymphocytes , and polymorphonucleate cells , but is markedly induced by interferon ; that PML and PML / RAR alpha expression is augmented by interferon in the NB 4 APL cell line , which carries the t ( 15 ; 17 ) , and in APL blasts from patients ; that interferon inhibits growth and survival of NB 4 APL cells in cooperation with RA ; that interferons alone have minimal maturation effect on NB 4 cells ; and , finally , that interferon gamma , but not alpha or beta , induces maturation and growth suppression of NB 4 cells with de novo retinoid resistance , and partially restores RA response . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
RAR alpha translocates in 99 % of cases to a gene located on chromosome 15 that we initially named myl and is now known as PML . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia with t ( 15 ; 16 ; 17 ; 19 ) and unusual fluorescence in situ hybridization pattern with PML and RARA probes . ^^^ RARA PML fusion was not evident by FISH , but the RARA signal was split in 74 . 5 % of cells . ^^^ GTL banding and FISH with probes for PML , RARA and chromosome 15 specific paint raise the possibility of PML RARA fusion on the abnormal chromosome 19 in the complex translocation . ^^^ The unusual PML RARA fusion may be related to this patient ' s poor response to induction therapy with all trans retinoic acid . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Fluorescence in situ hybridization ( FISH ) using cosmidic probes specific for RAR alpha and PML , regions did not show a fusion signal as in APL . ^^^ Detailed molecular analyses did not reveal any involvement of RAR alpha and PML genes . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Altered myeloid development and acute leukemia in transgenic mice expressing PML RAR alpha under control of cathepsin G regulatory sequences . ^^^ A balanced t ( 15 ; 17 ) ( q 22 ; q 21 ) reciprocal chromosomal translocation is found in approximately 90 % of APML patients ; this translocation fuses the PML gene on chromosome 15 to the retinoic acid receptor alpha ( RAR alpha ) gene on chromosome 17 , creating two novel fusion genes , PML RAR alpha and RAR alpha PML . ^^^ The PML RAR alpha fusion gene product , which is expressed in virtually all patients with t ( 15 ; 17 ) , is thought to play a direct role in the pathogenesis of APML . ^^^ To determine whether PML RAR alpha is sufficient to cause APML in an animal model , we used the promyelocyte specific targeting sequences of the human cathepsin G ( hCG ) gene to direct the expression of a PML RAR alpha cDNA to the early myeloid cells of transgenic mice . ^^^ Mice expressing the hCG PML RAR alpha transgene were found to have altered myeloid development that was characterized by increased percentages of immature and mature myeloid cells in the peripheral blood , bone marrow , and spleen . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
In most cases , Acute Promyelocytic Leukemia ( APL ) is associated with t ( 15 ; 17 ) translocation which juxtaposes sequences from PML and retinoic acid receptor alpha ( RAR alpha ) genes . ^^^ The generated PML RAR alpha fusion interferes with wild type RAR alpha mediated transcription and disrupts subnuclear compartments , known as PML bodies . ^^^ Although PLZF RAR alpha and PML RAR alpha are similar in their apparent dominant negative effects , t ( 11 ; 17 ) associated APL is refractory to ATRA therapy . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Variant complex translocations involving chromosomes 1 , 9 , 9 , 15 and 17 in acute promyelocytic leukemia without RAR alpha / PML gene fusion rearrangement . ^^^ Acute promyelocytic leukemia ( APL ; M 3 ) is specifically characterized by a predominance of malignant promyelocytes having atypical reciprocal translocation involving chromosome 15 and 17 [ t ( 15 ; 17 ) ( q 22 ; q 11 ) ] resulting in the fusion of retinoic acid receptor alpha ( RAR alpha ) on chromosome 17 and the putative transcription factor gene PML , ie the translocation generates two fusion transcripts , PML / RAR alpha and RAR alpha / PML . ^^^ The cytogenetic findings with GTG banding coupled with FISH analysis revealed the following karyotype : 46 , 20 , der ( 9 ) t ( 1 ; 9 ) ( q 25 ; q 34 ) der ( 9 ) t ( 9 ; ? ) ( q 34 ; ? ) , t ( 15 ; 17 ) ( q 22 ; q 11 ) ish . der ( 9 ) t ( 1 ; 9 ) ( q 25 ; q 34 ) ( WCP1+ , WCP9+ ) , t ( 9 ; 17 ; 15 ) ( q 34 ; q 11 ; q 22 ) ( WCP9+ , WCP15+ , PML+ ; WCP17+ , RAR alpha + ; WCP15+ , WCP17+ , PML ) [ 20 ] / 46 , 20 [ 5 ] . ^^^ However , chromosome 15q including the PML gene normally translocating to 17q and creating the RAR alpha / PML fusion gene , translocated to chromosome 9q . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APL ) is associated with the t ( 15 ; 17 ) translocation , which generates a PML / RAR alpha fusion protein between PML , a growth suppressor localized on nuclear matrix associated bodies , and RAR alpha , a nuclear receptor for retinoic acid ( RA ) . ^^^ PML / RAR alpha was proposed to block myeloid differentiation through inhibition of nuclear receptor response , as does a dominant negative RAR alpha mutant . ^^^ In addition , in APL cells , PML / RAR alpha displaces PML and other nuclear body ( NB ) antigens onto nuclear microspeckles , likely resulting in the loss of PML and / or NB functions . ^^^ RA leads to clinical remissions through induction of terminal differentiation , for which the respective contributions of RAR alpha ( or PML / RAR alpha ) activation , PML / RAR alpha degradation , and restoration of NB antigens localization are poorly determined . ^^^ In APL cells , arsenic targets PML and PML / RAR alpha onto NB and induces their degradation . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
In APL , one of the RAR genes , RARA , is fused to PML in the great majority of patients as a result of the chromosomal translocation t ( 15 ; 17 ) . ^^^ Current data suggest that PML RAR alpha and PLZF RAR alpha fusion receptors may play an important role in the development of APL and that PML RAR alpha could be the target of ATRA differentiation therapy . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The malignant cells of acute promyelocytic leukemia ( APL ) contain a reciprocal chromosomal translocation that fuses the promyelocytic leukemia gene ( PML ) with the retinoic acid receptor alpha gene ( RAR alpha ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Characterisation of the PML / RAR alpha rearrangement associated with t ( 15 ; 17 ) acute promyelocytic leukaemia . ^^^ The vast majority of cases of APL are associated with t ( 15 ; 17 ) leading to the formation of PML RAR alpha , RAR alpha PML and aberrant PML fusion products . ^^^ PML RAR alpha is invariably transcribed and is believed to mediate leukaemogenesis . ^^^ In APL the nuclear bodies become disrupted , presumably as a consequence of the presence of PML RAR alpha and aberrant PML proteins that might render the structure unstable . ^^^ PML RAR alpha is capable of binding RXR and sequestering it into the disrupted nuclear domains . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
We have shown recently that a retrovirus vector expressing a natural mutant form of the PML RAR alpha protein characteristic of human acute promyelocytic leukaemia can transform early chicken hematopoietic progenitors ( Altabef et al . , 1996 ) . ^^^ Neither truncated PML nor truncated RAR alpha alone could induce transformation which suggest that the two domains should cooperate for the oncogenicity of the fusion product . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
A retinoid resistant acute promyelocytic leukemia subclone expresses a dominant negative PML RAR alpha mutation . ^^^ The unique t ( 15 ; 17 ) of acute promyelocytic leukemia ( APL ) fuses the PML gene with the retinoic acid receptor alpha ( RAR alpha ) gene . ^^^ In the RA resistant subclone , R 4 , we find an absence of ligand binding of PML RAR alpha associated with a point mutation changing a leucine to proline in the ligand binding domain of the fusion PML RAR alpha protein . ^^^ In vitro expression of a cloned PML RAR alpha with the observed mutation in R 4 confirms that this amino acid change causes the loss of ligand binding , but the mutant PML RAR alpha protein retains the ability to heterodimerize with RXR alpha and thus to bind to retinoid response elements ( RAREs ) . ^^^ We then found that the mutant PML RAR alpha selectively alters regulation of gene expression in the R 4 cell line . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The chromosomal translocation ( 15 ; 17 ) which produced the PML RAR alpha fusion gene had been found in acute promyelocytic leukemia ( APL ) cells . ^^^ It was identified that the RAR alpha gene on chromosome 17 and PML gene on chromosome 15 were involved in this translocation . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
RAR alpha1 / RAR alpha 2 PML mRNA expression in acute promyelocytic leukemia cells : a molecular and laboratory clinical correlative study . ^^^ In addition to the major fusion gene PML RAR alpha , the t ( 15 ; 17 ) in acute promyelocytic leukemia ( APL ) produces the reciprocal fusion gene RAR alpha PML . ^^^ To determine the scope of RAR alpha containing mRNA expression in APL cells , we tested PML RAR alpha positive APL cells for the presence of mRNAs initiated from two distinct RAR alpha gene promoters , alpha 1 and alpha 2 . ^^^ From the translocated allele , RAR alpha 1 PML mRNA was expressed in 77 % and RAR alpha 2 PML mRNA in 28 % of cases ( N = 98 ) . ^^^ RAR alpha 2 PML mRNA was not observed in the absence of RAR alpha 1 PML mRNA . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APL ) has been characterized by 15 ; 17 chromosomal translocation , which involves the retinoic acid receptor alpha ( RARA ) gene on chromosome 17 and the PML gene on chromosome 15 . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
In human acute promyelocytic leukemia ( APL ) , RAR alpha becomes an activated oncogene as a consequence of its fusion to the PML locus . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Opposite effects of the acute promyelocytic leukemia PML retinoic acid receptor alpha ( RAR alpha ) and PLZF RAR alpha fusion proteins on retinoic acid signalling . ^^^ Fusion proteins involving the retinoic acid receptor alpha ( RAR alpha ) and the PML or PLZF nuclear protein are the genetic markers of acute promyelocytic leukemias ( APLs ) . ^^^ APLs with the PML RAR alpha or the PLZF RAR alpha fusion protein are phenotypically indistinguishable except that they differ in their sensitivity to retinoic acid ( RA ) induced differentiation : PML RAR alpha blasts are sensitive to RA and patients enter disease remission after RA treatment , while patients with PLZF RAR alpha do not . ^^^ These data demonstrate that PML RAR alpha and PLZF RAR alpha have similar ( inhibitory ) effects on RA independent differentiation and opposite ( stimulatory or inhibitory ) effects on RA dependent differentiation and that they behave in vivo as RA dependent enhancers or inhibitors of RA responsive genes , respectively . ^^^ Their different activities on the RA signalling pathway might underlie the different responses of PML RAR alpha and PLZF RAR alpha APLs to RA treatment . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
To study mechanism of chromosomal translocation , we analyzed the breakpoints ( b / p ) of the PML and RARA genes in 120 and 5 patients with de novo and secondary ( therapy related ) acute promyelocytic leukemia ( APL ) , respectively . ^^^ In studied 8 de novo APL patients , no consensus sequence motif was found around the b / p , but there were identical stretches of one to seven nucleotides between the PML and RARA genes in the joining regions , suggesting non selective DNA double strand cleavage followed by single strand base pairing within identical short stretches as a molecular mechanism of the translocation . ^^^ In 4 secondary APL patients after chemotherapy including etoposide against Langerhans cell histiocytosis , the b / p of the PML gene were located in intron 6 , and those of the RARA gene were in a restricted region within intron 2 , 1 kb EcoRI BamHI fragment , while in an APL patient after chemotherapy without etoposide against breast cancer , the b / p of the PML and RARA genes were located in intron 6 and another region within intron 2 , respectively . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The bcr 1 and bcr 3 promyelocytic leukemia / retinoic acid receptor alpha ( PML / RAR alpha ) are the two major fusion proteins expressed in acute promyelocytic leukemia ( APL ) patients . ^^^ These proteins , which are present in different lengths of PML ( amino acids 1 552 and 1 394 , respectively ) , contain most of the functional domains of PML and RAR alpha , bind all trans retinoic acid ( t RA ) , and act as t RA dependent transcription factors . ^^^ T RA is an effective inducer of clinical remission only in patients carrying the t ( 15 ; 17 ) and expressing the PML / RAR alpha products . ^^^ However , in APL patients achieving complete remission with t RA therapy the bcr 3 PML / RAR alpha product has been found associated with a poorer prognosis than bcr 1 PML / RAR alpha . ^^^ In the present study we have investigated the structural and functional properties of the bcr 3 PML / RAR alpha in comparison to the previously characterized bcr 1 PML / RAR alpha . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Association of PML RAR alpha fusion mRNA type with pretreatment hematologic characteristics but not treatment outcome in acute promyelocytic leukemia : an intergroup molecular study . ^^^ In each case of acute promyelocytic leukemia ( APL ) one of three PML RAR alpha mRNA types is produced , depending on the break / fusion site in the PML gene that is linked to a common RAR alpha gene segment : a short ( S ) form type , PML exon 3 RAR alpha exon 3 ; a long ( L ) form type , PML exon 6 RAR alpha exon 3 ; or a variable ( 5 ) form type , variably deleted PML exon 6 RAR alpha exon 3 . ^^^ We evaluated whether PML RAR alpha mRNA type is associated with distinct pretreatment clinical characteristics and therapeutic outcome in previously untreated adult APL patients registered to protocol INT 0129 by the Eastern Cooperative Oncology Group , the Southwest Oncology Group , and the Cancer and Leukemia Group B . ^^^ Nine cases not excluded by central pathology review were PML RAR alpha negative , and notably , none of five of these cases treated with ATRA achieved complete remission ( CR ) . ^^^ Among 221 PML RAR alpha positive cases , there were 82 S form cases ( 37 % ) , 121 L form cases ( 55 % ) , and 18 5 form cases ( 8 % ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Identification of classic and complex t ( 15 ; 17 ) and / or RAR alpha / PML gene fusion in APL by cytogenetic and dual color FISH techniques . ^^^ Acute promyelocytic leukemia ( APL ) is a malignant condition characterized by t ( 15 ; 17 ) ( q 22 ; q 12 ) , which fuses the PML gene on chromosome 15 to the retinoic acid receptor alpha ( RAR alpha ) gene on chromosome 17 . ^^^ In this study , t ( 15 ; 17 ) was identified cytogenetically by using the conventional cytogenetic technique , and its molecular counterpart RAR alpha / PML fusion on chromosome 17 on interphase nuclei was further confirmed by means of dual color ( DC ) fluorescence in situ hybridization ( FISH ) on serial bone marrow ( BM ) and peripheral blood ( PB ) samples from APL patients at different stages of the disease . ^^^ Overall , our findings indicate that interphase DC FISH analysis can be a useful technique as an adjunct to conventional cytogenetic investigation for detecting the presence of RAR alpha / PML fusion in APL . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
In more than 99 % of cases , this disruption results in the formation of a PML RARA gene fusion . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The acute promyelocytic leukemia ( APL ) t ( 15 ; 17 ) rearrangement fuses the promyelocytic leukemia ( PML ) gene to the retinoic acid receptor alpha ( RAR alpha ) . ^^^ There is expression of the chimeric transcript , PML / RAR alpha , in these APL cells . ^^^ The NB 4 APL cell line expresses PML / RAR alpha and responds to the growth inhibitory and differentiation inducing signals of ATRA . ^^^ When cultured in ATRA , these resistant cells still express PML , RAR alpha , and PML / RAR alpha proteins . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukaemia ( APL ) is a distinct entity of acute myeloid leukaemia characterized by blast cell morphology , severe coagulopathy and t ( 15 ; 17 ) translocation that fuses the PML gene on chromosome 15 to the retinoic acid receptor alpha ( RAR alpha ) gene on chromosome 17 . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
APL was further characterized by a specific sensitivity to all trans retinoic acid ' s differentiation effect and the production of a fusion gene altering the gene of RAR alpha and a gene called PML . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
RAR alpha translocates in 99 % of cases to a gene located on chromosome 15 that we initially named myl and subsequently has been called PML . ^^^ In fact , mice harboring a PML / RAR alpha transgene whose expression is specifically targeted to the myeloid promyelocytic lineage develop acute myeloid leukemia with promyelocytic features . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
PML is a nuclear protein with growth suppressive properties originally identified in the context of the PML retinoic acid receptor alpha ( RAR alpha ) fusion protein of acute promyelocytic leukemia . ^^^ PML localizes within distinct nuclear structures , called nuclear bodies , which are disrupted by the expression of PML RAR alpha . ^^^ We report that PML colocalizes with the nonphosphorylated fraction of the retinoblastoma protein ( pRB ) within nuclear bodies and that pRB is delocalized by PML RAR alpha expression . ^^^ Both PML and PML RAR alpha form complexes with the nonphosphorylated form of pRB in vivo , and they interact with the pocket region of pRB . ^^^ The regions of PML and PML RAR alpha involved in pRB binding differ ; in fact , the B boxes and the C terminal region of PML , the latter of which is not present in PML RAR alpha , are essential for the formation of stable complexes with pRB . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukaemia ( APL ) , associated with chromosomal translocations involving the retinoic acid receptor alpha gene ( RARA ) and the PML gene , is sensitive to retinoic acid ( RA ) treatment , while APL patients harbouring translocations between RARA and the PLZF gene do not respond to RA . ^^^ We have generated PML RARA and PLZF RARA transgenic mice and show here that these fusion proteins play a critical role in leukaemogenesis and in determining responses to RA in APL , because PLZF RARA transgenic mice develop RA resistant leukaemia , while PML RARA mice are responsive to RA treatment . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
However , treatment with RA induces differentiation of leukaemic blast cells and disease remission in PML RARalpha APLs , whereas PLZF RARa APLs are resistant to RA . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Fluorescence in situ hybridization with cosmid DNA probes flanking the breakpoints of t ( 15 ; 17 ) did not show the retinoic acid receptor alpha ( RAR alpha ) / PML fusion signal usually generated on the der ( 17 ) t ( 15 ; 17 ) . ^^^ However , rearrangement of the RAR alpha gene and expression of the PML / RAR alpha chimeric transcript were identified by Southern blot and reverse transcriptase polymerase chain reaction ( RT PCR ) analyses , respectively . ^^^ Our results confirmed that the PML / RAR alpha gene on the der ( 15 ) t ( 15 ; 17 ) , not the RAR alpha / PML gene , must be essential to leukemogenesis in APL . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The PML RAR alpha fusion gene plays an important role in leukemogenesis through antagonizing retinoic acid signalling and the regulatory pathways mediated by PML . ^^^ The therapeutic effect of ATRA in APL has been associated with the direct modulation of PML RAR alpha , the restoration of the differentiation pathways regulated by wild type RAR / retinoid 10 receptor heterodimer and PML . ^^^ Modulation and degradation of PML RAR alpha proteins can be induced by As2O3 and probably contribute to these two effects . ^^^ These studies lead to a model in which PML RAR alpha could be the target of both ATRA differentiation therapy and As2O3 apoptosis therapy . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukaemia is characterized by translocations that involve the retinoic acid receptor alpha ( RAR alpha ) locus on chromosome 17 and the PML locus on 15 or the PLZF locus on 11 . ^^^ The resulting abnormal translocation products encode for PML / RAR alpha or PLZF / RAR alpha fusion proteins . ^^^ There is increasing experimental evidence that the APL specific fusion proteins have similar biologic activities on differentiation and survival and that both components of the fusion proteins ( PML or PLZF and RAR alpha ) are indispensable for these biological activities . ^^^ We report here immunofluorescence studies on the cellular localization of PLZF and PLZF / RAR alpha and compare it with the localization of PML and PML / RAR alpha . ^^^ Expression of PLZF / RAR alpha did not provoke disruption of the PML NBs . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The differentiation inducing effects of 9CTT were inhibited by RAR antagonists . 9CTT and TT similarly induced the transactivating activity of RARs , but were not effective on RXRs . 9CTT downregulated the expression of PML / RAR alpha protein more effectively than TT , which suggests that it may be involved in the selectivity of 9CTT against APL cells . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
In vitro response to all trans retinoic acid of acute promyelocytic leukemias with nonreciprocal PML / RARA or RARA / PML fusion genes . ^^^ Acute promyelocytic leukemia ( APL ) is characterized by the t ( 15 ; 17 ) cytogenetic abnormality leading to the expression of two fusion genes , PML / RARA and RARA / PML , and by its sensitivity to all trans retinoic acid ( ATRA ) differentiating treatment . ^^^ We have previously reported two cases presenting with submicroscopic insertions of RARA or PML into chromosome 15 or 17 , respectively . ^^^ These insertions lead to the formation of potentially functional , nonreciprocal , PML / RARA or RARA / PML fusion genes , providing the unique opportunity to investigate in a human noncell line model the respective role of PML / RARA or RARA / PML in retinoid signaling . ^^^ Here , we report the in vitro response to ATRA of these two cases as well as of a third case presenting with submicroscopic insertion ( 15 ; 17 ) and expressing exclusively PML / RARA , by morphological , functional , and immunological assays . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APL ) originate from chromosomal translocations generating two types of fusion proteins both involving the retinoic acid receptor alpha ( RAR alpha ) and either the gene PML ( t ( 15 ; 17 ) ) or PLZF ( t ( 11 ; 17 ) ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Terminal deletion of the long arm of chromosome 9 in acute promyelocytic leukemia with a cryptic PML / RAR alpha rearrangement . ^^^ FISH with cosmid DNA probes flanking the breakpoints of t ( 15 ; 17 ) did not show the retinoic acid receptor alpha ( RAR alpha ) / PML fusion signal usually generated on the der ( 17 ) t ( 15 ; 17 ) . ^^^ However , rearrangement of the RAR alpha gene and expression of the PML / RAR alpha chimeric transcript were identified by Southern blot and reverse transcriptase polymerase chain reaction analyses , respectively . ^^^ These results suggested that the PML / RAR alpha fusion gene was generated by submicroscopic interstitial insertion of the RAR alpha gene into the PML gene . ^^^ Therefore , 9q was interpreted as a secondary aberration following the PML / RAR alpha rearrangement . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
At the molecular level , it fuses genes encoding PML on chromosome 15 and the nuclear retinoic acid receptor alpha ( RAR alpha ) on chromosome 17 . ^^^ The subsequent expression of PML / RAR alpha fusion mRNA provides a potential molecular marker that can be detected in leukemic cells taken from patients with APL . ^^^ Using PML and RARa sequence specific primers , reverse transcription polymerase chain reaction ( RT PCR ) assays have been developed for detection of PML / RAR alpha transcript in leukemic cells obtained from patients ; these RT PCR assays are more sensitive than conventional cytogenetic analysis . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Typical acute promyelocytic leukemia ( APL ) is associated with the t ( 15 ; 17 ) translocation , expression of a PML / RARA fusion transcript , and responsiveness to all trans retinoic acid ( ATRA ) . ^^^ Rare APL cases implicating the RARA but not the PML gene have been reported . ^^^ We described previously an APL case with an unbalanced t ( 5 ; 17 ) implicating RARA but neither PML nor PLZF . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukaemia ( APL ) exhibits a characteristic t ( 15 ; 17 ) translocation that fuses the promyelocytic leukaemia ( PML ) gene on 15q22 to the retinoic acid receptor alpha ( RARA ) gene on 17q12 q21 . 1 . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
In the present article , two new types of PML / RARA junctions are described . ^^^ By using different sets of primers , reverse transcriptase polymerase chain reaction ( RT PCR ) of PML / RARA junctions showed atypical larger bands compared with those generated from the three classical PML breakpoints already described . ^^^ This analysis showed two new hybrid transcripts that were 53 and 306 base pairs ( bp ) longer than that expressed by the NB 4 cell line ( PML breakpoint within intron 6 ) , and are the result of the direct joining of RARA exon 3 with PML exon 7a ( patient 2 ) or the 5 ' portion of PML exon 7b ( patient 1 ) , respectively . ^^^ In patient 1 , RT PCR analysis of the reciprocal RARA / PML junction showed a smaller transcript than that expected in bcr 1 cases , while in patient 2 no amplified fragment was obtained . ^^^ The clinical and hematological profiles expressed by the two patients carrying these unexpected types of PML / RARA rearrangement did not differ significantly from that commonly seen in other APLs with the exception of the poor outcome . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Formation of PML / RAR alpha high molecular weight nuclear complexes through the PML coiled coil region is essential for the PML / RAR alpha mediated retinoic acid response . ^^^ RA sensitivity in APL is mediated by its oncogenic protein , which results from the recombination of the PML and the RA receptor alpha ( RAR alpha ) genes ( PML / RAR alpha fusion protein ) . ^^^ Ectopic expression of PML / RAR alpha into haemopoietic cell lines results in increased response to RA induced differentiation . ^^^ By structure function analysis of PML / RAR alpha mediated RA differentiation , we demonstrated that fusion of PML and RAR alpha sequences and integrity of the PML dimerization domain and of the RAR alpha DNA binding region are required for the effect of PML / RAR alpha on RA differentiation . ^^^ Indeed , direct fusion of the PML dimerization domain to the N or C terminal extremities of RAR alpha retained full biological activity . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
PML and Tif1a are fused to RARA and Braf , respectively , resulting in the production of PML RARalpha and Tif1alpha B Raf ( T 18 ) oncoproteins . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
PML RARA fusion transcripts in irradiated and normal hematopoietic cells . ^^^ In this work we sought to investigate whether PML RARA fusion transcripts , characteristic of acute promyelocytic leukemia ( APL ) , could be induced by a clastogenic agent in cells known to have , a priori , a favorable spatial distribution of these genes . ^^^ A lymphoid cell line , lacking the t ( 15 ; 17 ) but having the PML and RARA genes in close proximity in specific phases of the cell cycle , was irradiated with 10 Gy of ( 60 ) Co , and the incidence of PML RARA transcripts was analyzed by a highly sensitive PCR assay . ^^^ Despite gene proximity , typical PML RARA transcripts were only rarely detected in irradiated cells . ^^^ PML RARA transcripts were observed at low frequencies in isolated lymphoid and granulocytic cell populations , with similar incidence in both cell types . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Of the four responders based on bone marrow morphology , two achieved molecular remission ( negative RT PCR for PML RAR alpha fusion transcripts ) by the end of the second and third cycles of As2O3 therapy . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
A mutated PML / RARA found in the retinoid maturation resistant NB 4 subclone , NB 4 R2 , blocks RARA and wild type PML / RARA transcriptional activities . ^^^ The fusion protein PML / RARA , associated with acute promyelocytic leukemia behaves as an abnormal retinoic acid ( RA ) receptor with altered transactivation properties but is still inducible by RA . ^^^ This has been supported by works reporting that in vitro ATRA resistance is characterized by defects in the RARA / E domain of PML / RARA . ^^^ In the present report , we identified a new mutation in the E domain of PML / RARA which is associated with a RA resistant subline of NB 4 cells ; NB 4 R2 . ^^^ This mutation , identical to the Gln 411 mutation found in HL 60 R , changes the amino acid Gln 903 to an in phase stop codon , generating a truncated form of PML / RARA which has lost 52 amino acids at its C terminal end . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The t ( 15 ; 17 ) translocation , which is a hallmark of this disease , results in a transcriptionally active fusion gene derived from the PML gene from chromosome 15 and the retinoic acid receptor alpha ( RARa ) gene from chromosome 17 . ^^^ The PML / RARa protein product is responsible for the leukemic phenotype in these patients , but is also able to respond to pharmacologic levels of retinoic acid and induce cell differentiation . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APL ) cells carry a mutated gene that is the result of a translocation in which the retinoic acid receptor alpha ( RAR alpha ) gene is fused to the promyelocytic leukemia ( PML ) gene , coding for a fusion protein , PML / RAR alpha . ^^^ All trans retinoic acid ( atRA ) induces the proteolytic degradation of PML / RAR alpha by ubiquitination and proteolysis . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
In contrast , PML RARalpha and PLZF RARa display an enhanced ability to form homodimers , and this enhanced homodimer formation is believed to contribute to the neoplastic properties of these chimeric oncoproteins . ^^^ We report here that the DNA recognition specificity of the RXRalpha / RARa heterodimer , which is presumed to be the dominant receptor species in normal cells , differs from that of the PML RARalpha and PLZF RARalpha homodimers , which are thought to prevail in the oncogenic cell . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APL ) is associated with chromosomal translocations , invariably involving the retinoic acid receptor alpha ( RAR alpha ) gene fused to one of several distinct loci , including the PML or PLZF genes , involved in t ( 15 ; 17 ) or t ( 11 ; 17 ) , respectively . ^^^ The PML RAR alpha and PLZF RAR alpha fusion oncoproteins function as aberrant transcriptional repressors , in part by recruiting nuclear receptor transcriptional corepressors and histone deacetylases ( HDACs ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APL ) is specifically associated with a reciprocal translocation , t ( 15 ; 17 ) ( q 22 ; q 21 ) , leading to the formation of a fusion of the retinoic acid receptor alpha ( RARA ) gene and the promyelocytic leukemia ( PML ) gene . ^^^ A submicroscopic PML RARA fusion was identified by reverse transcriptase polymerase chain reaction ( RT PCR ) and fluorescent in situ hybridization ( FISH ) . ^^^ The present study shows the key role of the fusion of PML RARA in the responsiveness to ATRA as well as in the leukemogenesis of APL . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
PML bodies are disrupted by PML retinoic acid receptor alpha ( RAR alpha ) oncoproteins in acute promyelocytic leukaemia . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Importantly , at both concentrations , As2O3 can degrade PML ( promyelocytic leukemia ) RAR alpha ( retinoic acid receptor ) , an oncoprotein that has a central role in leukemogenesis . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
We previously developed a murine model of acute promyelocytic leukemia ( APL ) by using human cathepsin G gene regulatory elements to direct the expression of promyelocytic leukemia ( PML ) / retinoic acid receptor alpha ( RAR alpha ) and RAR alpha / PML fusion cDNAs to the early myeloid compartment of transgenic mice . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Pilot study of PML / RAR alpha fusion by fluorescence in situ hybridization ( FISH ) method in acute promyelocyte leukemia ] . ^^^ BACKGROUND : Acute promyelocytic leukemia ( APL ) is characterized cytogenetically by t ( 15 ; 17 ) ( q 22 ; q 21 ) and its molecular consequence , fusion of PML and RAR alpha genes . ^^^ AIM : To evaluate the FISH method to detect PML / RAR alpha fusion , compared to cytogenetic analysis . ^^^ PATIENTS AND METHODS : Fifteen bone marrow specimens from APL patients with previous cytogenetic analysis were studied , using a commercial probe to detect PML / RAR alpha fusion . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
It harbors the ( 15 ; 17 ) translocation , which fuses the PML and RARA genes . ^^^ Moreover , we have performed dual color FISH by use of specific PML and RARA probes , to evaluate the number of copies for each gene and fusion gene . ^^^ Interestingly , the number of copies of PML , RARA , and fusion genes was different for each cell line . ^^^ Finally , we assessed the presence of the PML , RARA , PML / RARA , and RARA / PML transcripts by RT PCR and of the PML / RARA and RARA proteins by Western blotting in all the cell lines . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The genomic breakpoints in the t ( 15 ; 17 ) ( q 22 ; q 21 ) , associated with acute promyelocytic leukemia ( APL ) , are known to occur within three different PML breakpoint cluster regions ( bcr ) on chromosome 15 and within RARA intron 2 on chromosome 17 ; however , the precise mechanism by which this translocation arises is unclear . ^^^ To clarify this mechanism , we ( 1 ) . assembled the sequence of RARA intron 2 , ( 2 ) . amplified and sequenced the genomic PML RARA junction sequences from 37 APL patients , and ( 3 ) . amplified and sequenced the reverse RARA PML genomic fusion in 29 of these cases . ^^^ There was no evidence that the location of a breakpoint in PML had any relationship to the location of the corresponding breakpoint in RARA . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Also , the clinical relapse of disease in 4 APL patients with reverted PML / RAR alpha positivity is consistent with the view that detection of PML / RARalpha by RT RCR in patients in remission implies a poor prognosis . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The chimeric gene product PML RAR alpha , the result of a reciprocal t ( 15 ; 17 ) translocation , plays an important role in the pathogenesis of acute promyelocytic leukemia ( APL ) . ^^^ Interphase FISH was performed in nine patients , and revealed the presence of PML RAR alpha fusion gene in all patients . ^^^ Metaphase FISH of the patient with normal karyotype revealed a juxtaposed PML RAR alpha fusion signal on one chromosome 17 homologue , an RAR alpha signal on the other chromosome 17 homologue , and one PML signal on each chromosome 15 homologue . ^^^ Moreover , 5 form of the PML RAR alpha transcript was detected , and a portion of RAR alpha intron 2 was found inserted in the breakpoint region . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Fluorescence in situ hybridization ( FISH ) analysis using the PML RARA DNA probe showed a positive signal pattern ( fusion ) in 100 % of 200 total interphase and metaphase cells examined , confirming the presence of the PML RARA rearrangement . ^^^ This unusual t ( 15 ; 17 ; 17 ) prompted us to investigate further using reverse transcription polymerase chain reaction with primers from the 3 ' and 5 ' regions of both the RARA and PML loci . ^^^ These studies showed that the PML RARA fusion was present , but the complementary fusion RARA PML , which is usually detectable , was absent . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
New highly sensitive fluorescence in situ hybridization method to detect PML / RARA fusion in acute promyelocytic leukemia . ^^^ We investigated a new fluorescence in situ hybridization ( FISH ) method to detect PML / RARA fusion and / or anomalies of the RARA gene ( alias RARalpha ) in interphase nuclei from patients with acute promyelocytic leukemia ( APL ) . ^^^ This method uses a commercially available product with two different colored fluorescent probes to detect both PML / RARA gene fusion products ( double fusion signal or dual color fluorescence in situ hybridization [ D FISH ] ) . ^^^ The results suggest that the new D FISH probe set can detect all t ( 15 ; 17 ) ( q 22 ; q 21 ) and all variant forms of this translocation associated with PML and RARA . ^^^ In addition , this FISH method can detect all alternate translocations involving RARA and not PML . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The reciprocal translocation between the long arms of chromosomes 15 and 17 , and the fusion between the retinoic acid receptor ( RARa ) gene , and PML gene , is unique to APL . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
RXR alpha aberrantly colocalized within each 10 RAR alpha ; colocalization of RXR alpha with promyelocytic leukemia ( PML ) RAR alpha resulted in reduced mobility of RXR alpha . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
In APL , a chromosomal translocation produces a chimeric protein between RAR alpha and a protein called promyelocyte leukemia protein ( PML ) . ^^^ PML RAR alpha works as a dominant negative receptor in the leukemic cells , interfering with the normal function of RAR alpha and / or PML , which in turn results in the arrest of cell maturation at the stage of promyelocytes . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
To date five different fusion partners of RARA have been identified , but the vast majority of cases are characterized by the presence of the t ( 15 ; 17 ) ( q 22 ; q 12 21 ) , which involves the promyelocytic leukaemia ( PML ) gene . ^^^ The detection of the PML RARA fusion gene by reverse transcription polymerase chain reaction ( RT PCR ) is routinely used for diagnosis and monitoring of minimal residual disease ( MRD ) . ^^^ In PML RARA positive APL about 70 % of patients are expected to be cured with a combination of ATRA and anthracycline based chemotherapy . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Comparative analysis of genes regulated by PML / RAR alpha and PLZF / RAR alpha in response to retinoic acid using oligonucleotide arrays . ^^^ Acute promyelocytic leukemia ( APL ) is associated with chromosomal translocations involving retinoic acid receptor alpha ( RAR alpha ) and its fusion partners including promyelocytic leukemia ( PML ) and promyelocytic leukemia zinc finger ( PLZF ) . ^^^ Using oligonucleotide arrays , we examined changes in global gene expression mediated by the ectopic expression of either PML / RAR alpha ( retinoid sensitive ) or PLZF / RAR alpha ( retinoid resistant ) in U 937 cells . ^^^ RA strongly up regulated these genes in PML / RAR alpha , but not in PLZF / RAR alpha expressing U 937 cells . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia with PML RARA fusion on 1 ( 17q ) and therapy related acute myeloid leukemia . ^^^ We describe a patient with acute promyelocytic leukemia ( APL ) and the karyotype 46 , 20 , 1 ( 17 ) ( q 10 ) with PML RARA fusion gene detected by fluorescence in situ hybridization ( FISH ) and nested reverse transcriptase polymerase chain reaction ( RT PCR ) . ^^^ FISH using dual color translocation probes for PML ( promyelocytic leukemia ) and RARA ( retinoic acid receptor alpha ) showed fusion signal for PML RARA on both arms of 1 ( 17q ) . ^^^ The patient attained complete remission ( CR ) with all trans retinoic acid treatment and became PML RARA negative . ^^^ One year later , while PML RARA negative on FISH and RT PCR , the patient presented with thrombocytopenia . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Differentiation response of acute promyelocytic leukemia cells and PML / RARa leukemogenic activity studies by real time RT PCR . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Fluorescence in situ hybridization has been shown to be a fast and effective method of detecting the PML / RARA fusion gene characteristic of acute promyelocytic leukemia in fresh blood and bone marrow samples . ^^^ Nuclei were extracted from core biopsies of the formalin fixed paraffin embedded tissue and fluorescence in situ hybridization was performed using a dual color , dual fusion PML / RARA probe . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
A sumoylation site in PML / RARA is essential for leukemic transformation . ^^^ Pathogenesis of acute promyelocytic leukemia ( APL ) has been proposed to involve transcriptional repression through enhanced corepressors binding onto RARA moieties of PML / RARA homodimers . ^^^ Unexpectedly , we show that the K 160 sumoylation site in the PML moiety of PML / RARA is required for efficient immortalization / differentiation arrest ex vivo , implying that RARA homodimerization is insufficient to fully immortalize primary hematopoietic progenitor cells . ^^^ Thus , transcriptional repression dependent on a specific sumoylation site in PML is critical for the APL phenotype , while forced RARA dimerization could control expansion of the myeloid compartment . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
To determine whether topoisomerase 2 was directly involved in mediating breaks of double stranded DNA at the observed translocation breakpoints , we used a functional in vitro assay to examine topoisomerase 2 mediated cleavage in the normal homologues of the PML and RARA breakpoints . ^^^ Short , homologous sequences in PML and RARA suggested the occurrence of DNA repair by means of the nonhomologous end joining pathway . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Diagnosis and monitoring of PML RARA positive acute promyelocytic leukemia by qualitative RT PCR . ^^^ As a result , the RARA and the promyelocytic leukemia ( PML ) genes are fused . ^^^ The use of reverse transcription polymerase chain reaction ( RT PCR ) for the detection of the PML RARA and RARA PML fusion genes is the only technique that defines the PML breakpoint type and that allows the definition of a correct strategy for subsequent minimal residual disease ( MRD ) monitoring . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
In APL the retinoic acid receptor alpha gene is rearranged and fused with a novel gene called PML . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Specific gene activation ( N myc , evi 1 ) or fusion genes such as the alpha retinoic acid receptor ( alpha RAR ) and pml have been identified as the specific cause of some cases of leukemia . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Leukemia with distinct phenotypes in transgenic mice expressing PML / RAR alpha , PLZF / RAR alpha or NPM / RAR alpha . ^^^ The RAR alpha gene fuses to variable partners ( PML , PLZF , NPM , NuMA and STAT5B : 10 genes ) leading to the expression of APL specific fusion proteins with identical RAR alpha moieties . ^^^ We compared the features of the leukemia observed in these TM with those in hCG PML / RAR alpha and hCG PLZF / RAR alpha TM . ^^^ This phenotype contrasts with what was observed in the hCG PML / RAR alpha TM model in which the leukemic phase was characterized by the proliferation of promyelocytic blasts . ^^^ Importantly , the NPM / RAR alpha oncoprotein was found to localize in the nucleolus , unlike PML / RAR alpha and PLZF / RAR alpha , thus possibly interfering with the normal function of NPM . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
This PML RAR alpha fusion protein is responsible for the proliferative and de differentiated phenotype of the leukemic cells and is the target of all trans retinoic acid ( ATRA ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( PML ) is characterized by a reciprocal translocation between chromosomes 15 and 17 resulting in a chimeric PML and retinoic acid receptor alpha ( RARA ) oncogene . ^^^ The resultant fusion protein ( PML / RARA ) is thought to block differentiation of bone marrow cells arrested at the promyelocytic stage . ^^^ We report a unique case of a PML / RARA positive APL patient exhibiting extensive monocytic differentiation after ATRA therapy as documented by morphology , flow cytometry , and FISH studies . ^^^ We discuss potential dual capability for granulocytic / monocytic differentiation of PML / RARA positive APL cells and implications of monocytic differentiation in the management of APL patients treated with ATRA . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The acute promyelocytic leukaemia ( APL ) specific chromosome 15 ; 17 translocation leads to the fusion of a newly identified putative transcription factor , PML , and the retinoic acid receptor alpha . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The importance of retinoids , both as chemopreventive agents of tumorigenesis and potent differentiation inducers of neoplastic cells , can only be emphasized by the recent finding that the t ( 15 ; 17 ) ( q 21 q 11 22 ) translocation , specifically associated with acute promyelocytic leukemia , also causes translocation of the retinoic acid receptor alpha gene and its fusion with with a new locus , myl , of unknown function . ( ABSTRACT TRUNCATED AT 250 WORDS ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukaemia ( APL ) has been ascribed to a chromosomal translocation event which results in a fusion protein comprising the PML protein and the retinoic acid receptor alpha . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia is associated with a t ( 15 ; 17 ) translocation that generates a fusion product between PML and the retinoic acid receptor alpha . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The rearrangements within the second intron of the retinoic acid receptor alpha and sixth intron ( bcr 1 ) , third intron ( bcr 3 ) and sixth exon ( bcr 2 ) of the PML gene were detected in all cases with acute promyelocytic leukemia . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Molecular analysis showed cells to have a chimera gene consisted of PML and retinoic acid receptor alpha genes . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The chromosome breakpoints of the t ( 15 ; 17 ) have been shown to involve the retinoic acid receptor alpha ( RAR a ) gene and the newly described PML gene on chromosomes 17 and 15 , respectively . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The nuclear retinoic acid receptor alpha gene , on chromosome 17 , is translocated to the PML gene region , on chromosome 15 , resulting in the synthesis of two fusion messenger ribonucleic acids , PML / RAR alpha and RAR alpha / PML , easily detected by the reverse transcriptase polymerase chain reaction . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
In patients with acute promyelocytic leukemia presenting with a reciprocal translocation of chromosome 17 to chromosome 15 , the breakpoint has been identified in the retinoic acid receptor alpha gene , which forms a fusion gene with a new gene termed myl , on chromosome 15 . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Rearrangement of retinoic acid receptor alpha and PML in promyelocytic blast crisis of Ph 1 chromosome positive chronic myelocytic leukemia with normal copies of chromosome 15 . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Although routine karyotypic studies were inconclusive , at t ( 15 ; 17 ) translocation was documented using Southern blot genotypic analysis and probes for the retinoic acid receptor alpha and pml genes . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
In particular , the breakpoint on chromosome 17 has been localized within the retinoic acid receptor alpha locus while the breakpoint on chromosome 15 has been localized within a new gene named PML . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Each of the remaining three patients , one of whom had t ( 15 ; 17 ) with a monoclonal rearrangement of the retinoic acid receptor alpha and PML genes , carried two missense mutations in a relatively small population of leukemia cells . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APL ) has been ascribed to a chromosomal translocation event which results in a fusion protein comprising the PML protein and retinoic acid receptor alpha . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
A retrovirus carrying the promyelocyte retinoic acid receptor PML RARalpha fusion gene transforms haematopoietic progenitors in vitro and induces acute leukaemias . ^^^ The promyelocyte ( PML ) retinoic acid receptor alpha ( RARalpha ) fusion gene results from a t ( 15 ; 17 ) chromosome translocation in acute promyelocytic leukaemia . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The translocation found in acute promyelocytic leukemia rearranges the promyelocytic leukemia gene ( PML ) on chromosome 15 with the retinoic acid receptor alpha ( RARalpha ) on chromosome 17 . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The RING finger promyelocytic leukemia ( PML ) protein is the product of the PML gene that fuses with the retinoic acid receptor alpha gene in the t ( 15 ; 17 ) translocation of acute promyelocytic leukemia . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Leukemia associated retinoic acid receptor alpha fusion partners , PML and PLZF , heterodimerize and colocalize to nuclear bodies . ^^^ In acute promyelocytic leukemia ( APL ) , the typical t ( 15 ; 17 ) and the rare t ( 11 ; 17 ) translocations express , respectively , the PML / RARalpha and PLZF / RARalpha fusion proteins ( where RARalpha is retinoic acid receptor alpha ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APL ) is characterized by a reciprocal 15 ; 17 chromosomal translocation , which fuses the promyelocytic leukemia ( PML ) and retinoic acid receptor alpha ( RARalpha ) genes , leading to the expression of the PML / RARalpha fusion oncoprotein . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The human protein PML , was first identified as part of a fusion protein with retinoic acid receptor alpha as found in the chromosomal translocation which gives rise to acute promyelocytic leukaemia . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia is characterized by the presence of a t ( 15 ; 17 ) chromosomal translocation which results in the expression of a chimeric gene product , PMLRAR alpha , consisting of an N terminal truncated retinoic acid receptor alpha fused to a C terminal truncated PML . ^^^ The data presented also demonstrate that GAL4 / PML can recruit PMLRAR alpha resulting in the retinoid inducible transcriptional activation of a GAL 4 responsive promoter , a function dependent on the presence of the coiled coil region of PMLRAR alpha . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
PML , a RING finger protein with tumor suppressor activity , has been implicated in the pathogenesis of acute promyelocytic leukemia that arises following a reciprocal chromosomal translocation that fuses the PML gene with the retinoic acid receptor alpha ( RARalpha ) gene . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The PML gene is fused to the retinoic acid receptor alpha ( RARalpha ) gene in chromosomal translocations associated with acute promyelocytic leukemia ( APL ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
APL is associated in 99 % of cases with a 15 ; 17 translocation that fuses the PML and Retinoic Acid Receptor alpha ( RARalpha ) genes . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
A unique mRNA produced by the t ( 15 ; 17 ) ( q 22 24 ; q 11 21 ) translocation in the leukemic cells of acute promyelocytic leukemia patients encodes a chimeric protein , PML / RARalpha , which is formed by the fusion of the retinoic acid receptor alpha ( RARalpha ) and the promyelocytic locus gene ( PML ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
PIC 1 / SUMO 1 modified PML retinoic acid receptor alpha mediates arsenic trioxide induced apoptosis in acute promyelocytic leukemia . ^^^ Fusion proteins involving the retinoic acid receptor alpha ( RARalpha ) and PML or PLZF nuclear protein are the genetic markers of acute promyelocytic leukemia ( APL ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
BACKGROUND : The development of a rapid and simple reverse transcription polymerase chain reaction ( RT PCR ) assay is described that identifies the promyelocytic leukemia retinoic acid receptor alpha ( PML RARa ) hybrid messenger RNA ( mRNA ) , a characteristic feature of acute promyelocytic leukemia ( APL ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
PML fuses with retinoic acid receptor alpha ( RARalpha ) in the t ( 15 ; 17 ) translocation that causes acute promyelocytic leukemia ( APL ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Potentiation of GATA 2 activity through interactions with the promyelocytic leukemia protein ( PML ) and the t ( 15 ; 17 ) generated PML retinoic acid receptor alpha oncoprotein . ^^^ The B box region of PML is retained in the PML RARalpha ( retinoic acid receptor alpha ) fusion protein generated by the t ( 15 ; 17 ) translocation characteristic of acute promyelocytic leukemia ( APL ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The promyelocytic leukemia ( PML ) gene encodes a putative tumor suppressor gene involved in the control of apoptosis , which is fused to the retinoic acid receptor alpha ( RARalpha ) gene in the vast majority of acute promyelocytic leukemia ( APL ) patients as a consequence of chromosomal translocations . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Inhibition of promyelocytic leukemia ( PML ) / retinoic acid receptor alpha and PML expression in acute promyelocytic leukemia cells by anti PML peptide nucleic acid . ^^^ The fusion protein promyelocytic leukemia ( PML ) / retinoic acid receptor ( RAR ) alpha is tightly linked to the pathogenesis of acute promyelocytic leukemia ( APL ) ; hence , it represents a tumor associated , transformation related molecule . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
A fusion between the promyelocytic leukemia ( PML ) protein and the retinoic acid receptor alpha ( RARalpha ) results in the transforming protein of acute promyelocytic leukemia , PML RARalpha . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
A few years later , excitement with APL was further enhanced by the discovery that a cytogenetic marker for this disease , the t ( 15 : 17 ) reciprocal chromosomal translocation , involves a fusion between the retinoic acid receptor alpha ( RARalpha ) gene and a previously unknown locus named promyelocytic leukemia ( PML ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
APL is associated with a reciprocal chromosomal translocation of chromosomes 15 and 17 , which results in a fusion protein comprising PML and the retinoic acid receptor alpha . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Inactivation of the IFN induced PML gene by its fusion to retinoic acid receptor alpha alters the normal localization of PML from the punctuate nuclear patterns of NBs to micro dispersed tiny dots and results in uncontrolled growth in Acute Promyelocytic Leukaemia . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The Retinoic acid receptor alpha ( RARalpha ) chimeric proteins PML , PLZF , NPM , and NuMA RARalpha have distinct intracellular localization patterns . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
For example , in acute promyelocytic leukaemia ( APL ) , reciprocal chromosomal translocations involving the retinoic acid receptor alpha ( RARalpha ) gene lead to the formation of two fusion genes : 10 RARalpha and RARalpha 10 ( where 10 is the alternative RARalpha fusion partner : PML , PLZF , NPM , NuMA and STAT 5b ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APL ) is characterized by a specific chromosome translocation t ( 15 ; 17 ) , which results in the fusion of the promyelocytic leukemia gene ( PML ) and retinoic acid receptor alpha gene ( RARalpha ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukaemia ( APL ) is characterised by chromosomal rearrangements of 17q21 , leading to fusion of the gene encoding retinoic acid receptor alpha ( RARalpha ) to a number of alternative partner genes ( 10 ) , the most frequent of which are PML ( > 95 % ) , PLZF ( 0 . 8 % ) and NPM ( 0 . 5 % ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The promyelocytic leukemia ( PML ) protein , whose fusion with retinoic acid receptor alpha is responsible for the tumorigenesis of acute promyelocytic leukemia , acts as a tumor suppressor in various types of human cancers . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APL ) is characterized by a translocation between the promyelocytic leukemia gene ( PML ) on chromosome 15 and the retinoic acid receptor alpha ( RARalpha ) gene on chromosome 17 . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Promyelocytic leukaemia ( PML ) protein , the product of the pml gene , is heterogeneously expressed in various normal and neoplastic tissues , and the fusion of the pml gene with retinoic acid receptor alpha is believed to be a central mechanism in acute PML tumourigenesis . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Retinoic acid receptor alpha fusion to PML affects its transcriptional and chromatin remodeling properties . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia is caused by chromosomal translocations , which in the large majority of cases generate the prototypic promyelocytic leukemia retinoic acid receptor alpha ( PML RARalpha ) an oncogenic fusion protein formed from the retinoic acid receptor alpha and the so called PML protein . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
In APL , expression of promyelocytic leukemia protein retinoic acid receptor alpha ( PML RARalpha ) fusion protein , owing to the t ( 15 ; 17 ) reciprocal translocation , leads to a block in the promyelocytic stage of differentiation . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The acute promyelocytic leukemia ( PML ) retinoic acid receptor alpha ( RARalpha ) fusion product recruits histone deacetylase ( HDAC ) and DNA methyltransferase ( DNMT ) activities on retinoic acid ( RA ) target promoters causing their silencing and differentiation block . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Homo oligomerization via a coiled coil ( C C ) domain has been shown to be necessary for the promyelocytic leukemia ( PML ) retinoic acid receptor alpha ( RARalpha ) fusion protein to acquire oncogenic potential in acute promyelocytic leukemia . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
This phenotype is induced by specific acute myeloid leukemia associated translocations , such as t ( 15 ; 17 ) and t ( 11 ; 17 ) , which involve an identical portion of the retinoic acid receptor alpha ( RARalpha ) and either the promyelocytic leukemia ( PML ) or promyelocytic zinc finger ( PLZF ) genes , respectively . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The translocation results in a fusion gene product , PML RARalpha , in which the PML gene fuses to the retinoic acid receptor alpha ( RARalpha ) gene . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
In fact , dominant negative activity may be very important in the development of many neoplastic diseases , including acute promyelocytic leukemia ( APL ) , where a t ( 15 ; 17 ) chromosomal translocation fuses the PML gene to the RAR gene , to produce a PML RAR fusion protein in large excess in the cell . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Southern genomic analysis demonstrated re arrangements of the retinoic acid receptor varies ; is directly proportional to ( RAR varies ; is directly proportional to ) and PML genes in the APL blasts at presentation but not in the M 2 ANLL marrow at relapse . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
In fact , dominant negative activity may be very important in the development of many neoplastic diseases , including acute promyelocytic leukemia ( APL ) , where a t ( 15 ; 17 ) chromosomal translocation fuses the PML gene to the RAR gene , to produce a PML RAR fusion protein in large excess in the cell . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Minimal residual disease detection in acute promyelocytic leukemia by reverse transcriptase PCR : evaluation of PML RAR alpha and RAR alpha PML assessment in patients who ultimately relapse . ^^^ Most patients with APL express del ( 17q ) derived RAR alpha PML transcripts as well as the putative leukemogenic PML RAR alpha associated with add ( 15q ) . ^^^ We have found that a nested RT PCR for RAR alpha PML affords greater sensitivity than that for PML RAR alpha , particularly in patients with the commonest breakpoint pattern . ^^^ The RAR alpha PML assay changed the PCR status of two patients in morphological remission ; in both cases disease contamination of bone marrow harvest specimens was detected . ^^^ Although parallel assessment of PML RAR alpha and RAR alpha PML can enhance minimal residual disease detection in APL , this study demonstrates that treatment strategies involving determination of PCR status post consolidation , even using RAR alpha PML in addition to the more conventional PML RAR alpha assay will fail to identify all patients at risk of relapse . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Detection of the t ( 15 ; 17 ) or its molecular consequence , the PML RAR alpha rearrangement , is critical for meaningful analysis of clinical trials involving patients with suspected acute promyelocytic leukaemia ( APL ) . ^^^ RT PCR successfully identified PML RAR alpha rearrangements in 93 / 100 patients , including 65 where only peripheral blood or post induction marrow samples were available for analysis and in 12 patients in whom cytogenetic assessment failed to demonstrate t ( 15 ; 17 ) due to poor quality metaphases ( 10 / 12 ) or as a reflection of cryptic PML RAR alpha rearrangements ( 2 / 12 ) . ^^^ Parallel employment of the RAR alpha PML assay confirmed expression of del ( 17q ) derived transcripts in 81 % and permitted determination of the PML breakpoint ( a potential independent prognostic variable ) in all 93 cases . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Both PML and PLZF RARalpha possess identical RAR sequences and inhibit ATRA induced gene transcription as well as cell differentiation . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Recent discoveries have identified key molecular events in the pathogenesis of acute promyelocytic leukemia ( APL ) , caused by chromosomal rearrangements of the transcription factor RAR ( resulting in a fusion protein with the product of other cellular genes , such as PML ) . ^^^ Oligomerization of RAR , through a self association domain present in PML , imposes an altered interaction with transcriptional co regulators ( NCoR / SMRT ) . ^^^ NCoR / SMRT are responsible for recruitment of histone deacetylases ( HDACs ) , which is required for transcriptional repression of PML RAR target genes , and for the transforming potential of the fusion protein . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Trivalent antimonials induce degradation of the PML RAR oncoprotein and reorganization of the promyelocytic leukemia nuclear bodies in acute promyelocytic leukemia NB 4 cells . ^^^ Acute promyelocytic leukemia ( APL ) is characterized by a specific t ( 15 ; 17 ) chromosomal translocation that fuses the genes encoding the promyelocytic leukemia protein ( PML ) and the retinoic acid receptor ( RAR ) . ^^^ The resulting PML RAR protein induces a block in the differentiation of the myeloid progenitor cells , which can be released by retinoic acid ( RA ) in vitro and in vivo . ^^^ Intriguingly , As2O3 was also shown to induce degradation of the PML RAR chimera and to reorganize PML nuclear bodies . ^^^ The mechanism of antimony action is likely to be similar to that of As2O3 , notably both substances induce the attachment of the ubiquitin like SUMO 1 molecule to the PML moiety of PML RAR . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
RAR and AML 1 transcription factors are found in leukemias as fusion proteins with PML and ETO , respectively . ^^^ Association of PML RAR and AML 1 ETO with the nuclear corepressor ( N CoR ) / histone deacetylase ( HDAC ) complex is required to block hematopoietic differentiation . ^^^ We show that PML RAR and AML 1 ETO exist in vivo within high molecular weight ( HMW ) nuclear complexes , reflecting their oligomeric state . ^^^ Fusion of RAR to a heterologous oligomerization domain recapitulated the properties of PML RAR , indicating that oligomerization per se is sufficient to achieve transforming potential . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
In acute promyelocytic leukemia , PML / retinoic acid receptor ( RAR ) alpha expression disrupts NBs , but therapies such as retinoic acid or arsenic trioxide ( As2O3 ) restore them . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Identification of two atypical PML RAR ( alpha ) transcripts in two patients with acute promyelocytic leukemia . ^^^ We identified two patients with atypical PML RAR ( alpha ) rearrangements , 53 and 13 base pairs longer than the typical bcr 1 transcript . ^^^ Sequence analysis revealed a new PML breakpoint at the end of exon 7a in patient 1 , and a PML exon 6 breakpoint in patient 2 , with an insertion of 35 nucleotides of RAR ( alpha ) intron 2 . ^^^ Patient 1 did not express RAR ( alpha ) PML and patient 2 showed the RAR ( alpha ) PML transcript , which corresponded to the typical bcr 1 . ^^^ These results emphasize on the relevance of the correct identification of atypical PML RAR ( alpha ) rearrangements because of the potential implications in leukemogenesis , in the response to treatment , and for the correct monitoring of minimal residual disease . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Variant type PML RAR ( alpha ) fusion transcript in acute promyelocytic leukemia : use of a cryptic coding sequence from intron 2 of the RAR ( alpha ) gene and identification of a new clinical subtype resistant to retinoic acid therapy . ^^^ In the great majority of patients with APL , RAR ( alpha ) is fused to the PML gene as a result of the t ( 15 ; 17 ) translocation . ^^^ Three distinct types of PML RAR ( alpha ) transcripts , long ( L ) , short ( S ) , and variant ( 5 ) , were identified . ^^^ The 5 type is characterized by truncation of exon 6 of PML and in some cases by the insertion of a variable `` spacer ' ' sequence between the truncated PML and RAR ( alpha ) mRNA fusion partners , although the precise mechanisms underlying formation of the 5 type transcript remain unclear . ^^^ In these cases , the aberrant 5 type PML RAR ( alpha ) protein displayed increased affinity to the nuclear corepressor protein SMRT , providing further evidence that RA exerts the therapeutic effect on APL through modulation of the RAR corepressor interaction . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Interestingly , two PML mutants , PML RAR and PMLDelta 216 331 , which fail to form PML NBs , could also coactivate Tax mediated trans acting function but had no effect on retinoic acid receptor ( RAR ) or p 53 dependent gene expression . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The promyelocytic leukemia ( PML ) protein is a potent growth suppressor and proapototic factor , whereas aberrant fusions of PML and retinoic acid receptor ( RAR ) alpha are causal agents in human acute promyelocytic leukemia . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Recent work shows that the leukemia associated fusion protein PML RAR can mediate both biological effects targeting independent pathways , through a unifying mechanism . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Whereas the retinoic acid receptor beta ( RARbeta ) rearrangement in hepatocellular carcinoma is unique , in acute promyelocytic leukemia ( APL ) , RARalpha fusion to the promyelocytic leukemia ( PML ) gene by the t ( 15 ; 17 ) translocation is a general feature of the disease . ^^^ The molecular basis of PML / RARalpha fusion leukemogenesis is discussed with respect to dominant negative inhibition of nuclear receptor and PML functions . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Effects on differentiation by the promyelocytic leukemia PML / RARalpha protein depend on the fusion of the PML protein dimerization and RARalpha DNA binding domains . ^^^ Expression of the APL specific PML / RARalpha fusion protein in hematopoietic precursor cell lines blocks terminal differentiation , suggesting that PML / RARalpha may have the same activity in APL blasts . ^^^ We expressed different PML / RARalpha mutants in U 937 and TF 1 cells and demonstrated that the integrity of the PML protein dimerization and RARalpha DNA binding domains is crucial for the differentiation block induced by PML / RARalpha , and that these domains exert their functions only within the context of the fusion protein . ^^^ Analysis of the in vivo dimerization and cell localization properties of the PML / RARalpha mutants revealed that PML / RARalpha PML and PML / RARalpha RXR heterodimers are not necessary for PML / RARalpha activity on differentiation . ^^^ We propose that a crucial mechanism underlying PML / RARalpha oncogenic activity is the deregulation of a transcription factor , RARalpha , through its fusion with the dimerization interface of another nuclear protein , PML . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
To further investigate the mechanisms of PLZF RARalpha action , we have also studied its ligand receptor , protein protein , and protein DNA interaction properties and compared them with those of the promyelocytic leukemia gene ( PML ) RARalpha , which is expressed in the majority of APLs as a result of t ( 15 ; 17 ) translocation . ^^^ PLZF RARalpha and PML RARalpha have essentially the same ligand binding affinities and can bind in vitro to retinoic acid response elements ( RAREs ) as homodimers or heterodimers with RXRalpha . ^^^ Despite having identical RARalpha sequences , PLZF RARalpha and PML RARalpha homodimers recognized with different affinities distinct RAREs . ^^^ These different protein protein interactions and the target gene specificities of PLZF RARalpha and PML RARalpha may underlie , at least in part , the apparent resistance of APL with t ( 11 ; 17 ) to differentiation effects of all trans retinoic acid . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Recently this leukemia was further characterized by an exquisite sensitivity to all trans retinoic acid ' s differentiation effect and the production of a fusion gene altering the gene of RARalpha and a novel gene PML . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The PML and PML / RARalpha domains : from autoimmunity to molecular oncology and from retinoic acid to arsenic . ^^^ Acute promyelocytic leukemia ( APL ) is specifically associated to a t ( 15 ; 17 ) translocation which fuses a gene encoding a nuclear receptor for retinoic acid , RARalpha , to a previously unknown gene PML . ^^^ In APL , the PML / RARalpha fusion interferes with both the retinoic acid ( RA ) response and PML localization on nuclear bodies , but the respective contribution of each defect to leukemogenesis is unclear . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute leukemia with promyelocytic features in PML / RARalpha transgenic mice . ^^^ In the majority of cases , RARalpha translocates and fuses with the promyelocytic leukemia ( PML ) gene located on chromosome 15 . ^^^ The resulting fusion genes encode the two structurally unique PML / RARalpha and RARalpha / PML fusion proteins as well as aberrant PML gene products , the respective pathogenetic roles of which have not been elucidated . ^^^ We have generated transgenic mice in which the PML / RARalpha fusion protein is specifically expressed in the myeloid promyelocytic lineage . ^^^ During their first year of life , all the PML / RARalpha transgenic mice have an abnormal hematopoiesis that can best be described as a myeloproliferative disorder . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
SMRT corepressor interacts with PLZF and with the PML retinoic acid receptor alpha ( RARalpha ) and PLZF RARalpha oncoproteins associated with acute promyelocytic leukemia . ^^^ Human acute promyelocytic leukemia , for example , is tightly linked to chromosomal translocations that fuse novel amino acid sequences ( denoted PML , PLZF , and NPM ) to the DNA binding and hormone binding domains of RARalpha . ^^^ We report here that the PML RARalpha and PLZF RARalpha oncoproteins retain the ability of RARalpha to associate with corepressors , and that this corepressor association correlates with certain aspects of the leukemic phenotype . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Cell death induction by the acute promyelocytic leukemia specific PML / RARalpha fusion protein . ^^^ PML / RARalpha is the abnormal protein product generated by the acute promyelocytic leukemia specific t ( 15 ; 17 ) . ^^^ Expression of PML / RARalpha in hematopoietic precursor cell lines induces block of differentiation and promotes survival . ^^^ We report here that PML / RARalpha has a potent growth inhibitory effect on all nonhematopoietic cell lines and on the majority of the hematopoietic cell lines tested . ^^^ Inducible expression of PML / RARalpha in fibroblasts demonstrated that the basis for the growth suppression is induction of cell death . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Mutant forms of RARalpha , created by chromosomal translocations with either the PML ( for promyelocytic leukaemia ) or the PLZF ( for promyelocytic leukaemia zinc finger ) locus , are oncogenic and result in human acute promyelocytic leukaemia ( APL ) . ^^^ PML RARalpha APL patients achieve complete remission following treatments with pharmacological doses of retinoic acids ( RA ) ; in contrast , PLZF RARalpha patients respond very poorly , if at all . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The growth and transformation suppressor function of promyelocytic leukemia ( PML ) protein are disrupted in acute promyelocytic leukemia ( APL ) as a result of its fusion to the RARalpha gene by t ( 15 ; 17 ) translocation . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APL ) is typified by the reciprocal translocation , t ( 15 ; 17 ) ( q 22 ; q 21 ) , leading to the formation of PML RARalpha and RARalpha PML fusion genes . ^^^ In 6 of 7 cases , cryptic PML RARalpha rearrangements were identified by reverse transcriptase polymerase chain reaction and fluorescent in situ hybridization ( FISH ) ; whereas , in the remaining patient , APL was associated with the variant translocation , t ( 11 ; 17 ) ( q 23 ; q 12 21 ) , leading to the formation of PLZF RARalpha and RARalpha PLZF fusion genes . ^^^ In each of the cases with cryptic PML RARalpha rearrangements , PML RARalpha transcripts were detected in the absence of RARalpha PML , consistent with the concept that PML RARalpha is the critical oncogenic fusion protein . ^^^ In 4 of these cases with evaluable metaphase spreads , the occurrence of a nonreciprocal translocation was confirmed by FISH with sole formation of the PML RARalpha fusion gene ; in 3 cases with morphologically normal chromosomes 15 and 17 , RARalpha was inserted into PML on 15q , whereas in the remaining patient the PML RARalpha fusion arose due to insertion of 15q derived material including PML into RARalpha on 17q . ^^^ In APL cases with cryptic PML RARalpha rearrangements , the characteristic microparticulate pattern of PML staining was detected with partial colocalization with PIC 1 , indicative of disruption of the nuclear bodies ; whereas in t ( 11 ; 17 ) associated APL , PML and PIC 1 remained colocalized within discrete nuclear bodies , as observed in non APL cases . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Leukemic cellular retinoic acid resistance and missense mutations in the PML RARalpha fusion gene after relapse of acute promyelocytic leukemia from treatment with all trans retinoic acid and intensive chemotherapy . ^^^ This study evaluated whether relapse of acute promyelocytic leukemia ( APL ) patients from clinical remissions achieved and / or maintained with all trans retinoic acid ( RA ) in combination with intensive chemotherapy is associated with leukemic cellular resistance to RA and with alterations in the PML RARalpha fusion gene . ^^^ From analysis of sequences encoding the principal functional domains of the PML and RARalpha portions of PML RARalpha , we found missense mutations in relapse specimens from 3 of 12 RA treated patients and 0 of 8 DA treated patients . ^^^ All 3 mutations were located in the ligand binding domain ( LBD ) of the RARalpha region of PML RARalpha . ^^^ No mutations were detected in the corresponding sequences of the normal RARalpha or PML ( partial ) alleles . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Our data on the breakpoints ( b / ps ) of the PML and RARalpha genes are presented . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
PML / RARalpha is the abnormal protein product of the Acute Promyelocytic Leukemia specific 15 ; 17 translocation . ^^^ Both the PML and RARalpha components are required for the PML / RARalpha biological activities , namely its capacity to block differentiation and to increase survival of haematopoietic precursors . ^^^ The PML aminoterminal portion retained within the PML / RARalpha protein contains the RING finger , two newly defined cystein / histidine rich motifs called B boxes ( B 1 and B 2 ) and a coiled coil region . ^^^ These results indicate that PML is involved in cell survival regulation and that the PML component of the fusion protein ( Ring + B 1 B2 and coiled coil regions ) retains intact biological activity , thereby suggesting that the effects of PML / RARalpha on survival derive from the activation of the incorporated PML sequence . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Greater than 95 % of acute promyelocytic leukemia ( APL ) cases are associated with the expression of PML RARalpha . ^^^ A small number of variant APL translocations have also been shown to involve rearrangements that fuse RARalpha to partner genes other than PML , namely PLZF , NPM , and NuMA . ^^^ We further explored the effects of the NPM RARalpha chimeric protein on the subcellular localization of PML , RXRalpha , NPM , and PLZF using immunofluorescent confocal microscopy . ^^^ Our data support the hypothesis that while deregulation of both the retinoid signaling pathway and RARalpha partner proteins are molecular consequences of APL translocations , APL pathogenesis is not dependent on disruption of PML nuclear bodies . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Although their mechanisms of action are believed to be distinct , these two drugs both induce the catabolism of the oncogenic promyelocytic leukemia ( PML ) / RARalpha fusion protein . ^^^ Using syngenic grafts of leukemic blasts from PML / RARalpha transgenic mice as a model for APL , we demonstrate that arsenic induces apoptosis and modest differentiation , and prolongs mouse survival . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
In acute promyelocytic leukemia NB 4 cells , the synthetic retinoid CD 437 induces contemporaneously apoptosis , a caspase 3 mediated degradation of PML / RARalpha protein and the PML retargeting on PML nuclear bodies . ^^^ Furthermore , it was demonstrated that the caspase 3 like proteolytic activity is responsible for the degradation of both the PML / RARalpha oncogenic protein and the normal RARalpha proteins . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The nuclear topography of ABL , BCR , PML , and RARalpha genes : evidence for gene proximity in specific phases of the cell cycle and stages of hematopoietic differentiation . ^^^ In this work , we have addressed this issue using as models the ABL and BCR genes of t ( 9 ; 22 ) and the PML and RARalpha genes of t ( 15 ; 17 ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
As a consequence of the translocation RARalpha variably fuses to the PML , PLZF , NPM and NUMA genes ( 10 genes ) , leading to the generation of RARalpha 10 and 10 RARalpha fusion genes . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Alternatively , displacement of ALK , RARalpha and PML to novel positions could lead to loss of their normal regulation . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Molecular analysis and clinical outcome of adult APL patients with the type 5 PML RARalpha isoform : results from intergroup protocol 0129 . ^^^ The type 5 ( for variable ) promyelocytic leukemia retinoic acid receptor ( PML RAR ) alpha transcript , found in approximately 8 % of adult patients with acute promyelocytic leukemia ( APL ) , is defined molecularly by truncation of PML exon 6 and frequent insertion of genetic material from RARalpha intron 2 . ^^^ To more fully characterize the molecular features of PML RARalpha 5 type transcripts and to determine whether 5 form APL patients have a distinct clinical presentation or prognosis , we analyzed 18 adult 5 form APL patients enrolled on Intergroup protocol 0129 ( INT 0129 ) . ^^^ Truncations in PML exon 6 ranged from 8 to 146 nucleotides , and 3 to 127 extra nucleotides ( 1 to 42 extra amino acids ) were inserted at the PML exon 6 / RARalpha exon 3 junction in 13 cases . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APL ) is characterized by a specific chromosome translocation involving RARalpha and one of four fusion partners : PML , PLZF , NPM , and NuMA genes . ^^^ Dissociation of SMRT from different receptors was observed at ATRA concentrations of 0 . 01 microM , 0 . 1 microM , and 1 . 0 microM for RARalpha RXRalpha , NPM RARalpha , and PML RARalpha , respectively , but not observed for PLZF RARalpha even in the presence of 10 microM ATRA . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The impact of differential binding of wild type RARalpha , PML , PLZF and NPM RARalpha fusion proteins towards transcriptional co activator , RIP 140 , on retinoic acid responses in acute promyelocytic leukemia . ^^^ The difference in response to ATRA therapy between acute promyelocytic leukemia ( APL ) patients with PML RARalpha fusion and PLZF RARalpha fusion has recently been found to be partially due to the strong association of the transcriptional co repressor , SMRT / N CoR , with PLZF domain . ^^^ We demonstrate that SMRT association , as with PML RARalpha , can be released from NPM RARalpha at pharmacological concentration of ATRA ( 10 6 M ) . ^^^ Moreover , we show for the first time that the interaction between the transcriptional co activator , RIP 140 , and PML , PLZF or NPM RARalpha fusion proteins can be positively stimulated by ATRA although they are less sensitive as compared with the wild type RARalpha . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APL ) is characterized by a specific translocation ( 15 ; 17 ) ( q 22 ; q 21 ) , resulting in the formation of PML / RARalpha chimeric transcripts . ^^^ We report two female patients with PML / RARalpha positive classical APL , whose leukemic cells expressed a variant translocation , t ( 5 ; 15 ) ( q 13 ; q 22 ) and t ( 15 ; 17 ) ( q 22 ; p 13 ) , respectively . ^^^ A two color fluorescence in situ hybridization with a 5 ' PML and a 3 ' RARalpha probe showed , in both cases , the presence of a PML RARalpha fusion gene , on the der ( 15 ) t ( 5 ; 15 ) long arm , and on the der ( 17 ) t ( 15 ; 17 ) short arm , respectively . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Retinoic acid ( RA ) and As2O3 treatment in transgenic models of acute promyelocytic leukemia ( APL ) unravel the distinct nature of the leukemogenic process induced by the PML RARalpha and PLZF RARalpha oncoproteins . ^^^ Acute promyelocytic leukemia ( APL ) is associated with chromosomal translocations always involving the RARalpha gene , which variably fuses to one of several distinct loci , including PML or PLZF ( 10 genes ) in t ( 15 ; 17 ) or t ( 11 ; 17 ) , respectively . ^^^ Here , we show that RA , As ( 2 ) O ( 3 ) , and RA + As ( 2 ) O ( 3 ) prolonged survival in either leukemic PML RARalpha transgenic mice or nude mice transplanted with PML RARalpha leukemic cells . ^^^ Unexpectedly , therapeutic doses of RA and RA + As ( 2 ) O ( 3 ) can induce , both in vivo and in vitro , the degradation of either PML RARalpha or PLZF RARalpha proteins , suggesting that the maintenance of the leukemic phenotype depends on the continuous presence of the former , but not the latter . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Altered ligand binding and transcriptional regulation by mutations in the PML / RARalpha ligand binding domain arising in retinoic acid resistant patients with acute promyelocytic leukemia . ^^^ Acute promyelocytic leukemia ( APL ) is characterized by a specific translocation , t ( 15 ; 17 ) , that fuses the promyelocytic leukemia ( PML ) gene with the RA receptor RARalpha . ^^^ Recently , mutations in PML / RARalpha have been described in APL cells from patients clinically resistant to RA therapy . ^^^ These mutant PML / RARalpha proteins have been expressed in vitro , which shows that they cause a diversity of alterations in binding to ligand and to nuclear coregulators of transcription , leading to varying degrees of inhibition of retinoid induced transcription . ^^^ This contrasts with the nearly complete dominant negative activity of mutations in PML / RARalpha previously characterized in cell lines developing RA resistance in vitro . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The breakpoints of chromosome 15 and 17 are in the PML and RARalpha genes , respectively , forming the fusion PML RARalpha gene expressed exclusively and universally in APL . ^^^ The aberrant fusion PML RARalpha protein remains sensitive to ATRA and underlies the pathogenesis of the APL . ^^^ ATRA modulation of gene transcription mediated by PML RARalpha results in a major clinical response . ^^^ PML RARalpha fusion transcripts can be assayed by RT PCR to identify PCR positive cells during remission , which are highly predictable of a subsequent haematological relapse . ^^^ The goal of therapy has been modified to induce a molecular remission with a negative PCR to the PML RARalpha transcript . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The fusion protein , promyelocytic leukemia retinoic acid receptor ( PML RAR ) alpha , generated by the t ( 15 ; 17 ) translocation has an abnormal cellular distribution with colocalization of RARalpha and PML proteins . ^^^ We analyzed the immunostaining pattern of PML protein using the PG M 3 monoclonal antibody directed against the amino terminal portion of PML ( retained in wild type PML and PML RARalpha fusion protein ) in the diagnosis of acute promyelocytic leukemia ( APL ) . ^^^ In addition , we compared this test with other methods for detecting the PML RARalpha fusion gene . ^^^ These results were concordant with the reverse transcriptase polymerase chain reaction results for PML RARalpha fusion gene . ^^^ Only 1 case positive for the PML RARalpha transcript showed a normal protein pattern by immunocytochemistry . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
However , no t ( 15 ; 17 ) , or RARalpha gene , MLL gene or PML gene rearrangement was observed , or any other cytogenetic clonal abnormality . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
We previously generated a transgenic mouse model for acute promyelocytic leukemia ( APL ) by expressing the promyelocytic leukemia ( PML ) retinoic acid receptor ( RARalpha ) cDNA in early myeloid cells . ^^^ PML RARalpha is therefore necessary , but not sufficient , for APL development . ^^^ The coexpression of a reciprocal form of the fusion , RARalpha PML , increased the likelihood of APL development ( 55 60 % ) , but did not shorten latency . ^^^ Interstitial or terminal deletions of the distal region of one copy of chromosome 2 [ del ( 2 ) ] were found in 1 / 5 tumors expressing PML RARalpha , but in 11 / 13 tumors expressing both PML RARalpha and RARalpha PML ( P < 0 . 05 ) . ^^^ These results suggest that expression of RARalpha PML increases the likelihood of chromosome 2 deletions in APL cells . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APL ) is associated with chromosomal translocations that always involve the RARalpha gene , which variably fuses to one of several distinct loci , including PML or PLZF ( 10 genes ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
In most cases of acute promyelocytic leukemia ( APL ) , a fusion of the promyelocytic leukemia ( PML ) and the retinoic acid receptor alpha ( RARalpha ) genes occurs , resulting in the expression of a PML RARalpha chimeric protein . ^^^ PLZF RARalpha positive APL forms a clinically distinct group because unlike PML RARalpha positive leukemia , it does not respond to retinoic acid with terminal granulocytic differentiation of the cells , and remissions can not be achieved with retinoids alone . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
RARalpha variably fuses to the PML , PLZF , NPM , NuMA , and STAT 5b genes ( 10 genes ) , leading to the generation of 10 RARalpha and RARalpha 10 fusion genes . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The majority of patients with acute promyelocytic leukemia ( APL ) possess either a bcr 1 or a bcr 3 type fusion between PML and RARalpha genes . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
RARalpha fuses to the PML gene in the vast majority of APL cases , and in a few cases to the PLZF , NPM , NuMA and Stat5b genes , respectively , leading to the generation of RARalpha 10 : and 10 : RARalpha fusion genes . ^^^ Here , it will be discussed in detail how an extensive biochemical analysis as well as a systematic in vivo genetic approach in the mouse has allowed the definition of the multiple oncogenic activities of PML RARalpha , and how it has become apparent that this oncoprotein is able to impair RARalpha at the transcription level and the tumor suppressive function of the PML protein . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The t ( 15 ; 17 ) translocation , found in 95 % of acute promyelocytic leukemia , encodes a promyelocytic leukemia ( PML ) retinoic acid receptor alpha ( RARalpha ) fusion protein . ^^^ Complete remission of acute promyelocytic leukemia can be obtained by treating patients with all trans retinoic acid , and PML RARalpha plays a major role in mediating retinoic acid effects in leukemia cells . ^^^ A main model proposed for acute promyelocytic leukemia is that PML RARalpha exerts its oncogenic effects by repressing the expression of retinoic acid inducible genes critical to myeloid differentiation . ^^^ By applying subtraction cloning to acute promyelocytic leukemia cells , we identified a retinoic acid induced gene , PRAM 1 ( PML RARalpha target gene encoding an Adaptor Molecule 1 ) , which encodes a novel adaptor protein sharing structural homologies with the SLAP 130 / fyb adaptor . ^^^ In U 937 myeloid precursor cells , PRAM 1 expression is inhibited by expression of PML RARalpha in the absence of ligand and de novo superinduced by retinoic acid . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
As a consequence of the translocation , RARalpha variably fuses to the PML , PLZF , NPM , NuMA , and Stat5b genes ( 10 genes ) , respectively , leading to the generation of RARalpha 10 and 10 RARalpha fusion genes . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute myeloblastic leukaemias of FAB types M 6 and M 4 , with cryptic PML / RARalpha fusion gene formation , relapsing as acute promyelocytic leukaemia M 3 . ^^^ Demonstration of either the translocation t ( 15 ; 17 ) ( q 22 ; q 21 ) or the fusion of PML and RARalpha genes is regarded as diagnostic for acute myeloid leukaemia ( AML ) of FAB type M 3 , but has occasionally been seen in other FAB types . ^^^ Fluorescence in situ hybridization ( FISH ) of metaphase chromosomes at diagnosis showed insertion of material from chromosome 17 into a ' normal ' 15 with juxtaposition of PML and RARalpha . ^^^ FISH analysis showed this to be a three way translocation involving chromosomes 15 , 16 and 17 again with juxtaposition of PML and RARalpha . ^^^ Reverse transcription polymerase chain reaction ( RT PCR ) revealed PML / RARalpha fusion at diagnosis , in remission and in first relapse . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Here we review how a detailed analysis of the functions of two of these RARalpha partners , the promyelocytic leukemia ( PML ) and promyelocytic leukemia zinc finger ( PLZF ) proteins , has allowed a greater understanding of the molecular mechanisms implicated in APL pathogenesis . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
RARalpha variably fuses to PML , PLZF , NPM , NuMA , and Stat5B genes ( 10 genes / proteins ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
RARalpha fuses to the PML gene in the vast majority of APL cases , and in a few cases to the PLZF , NPM , NuMA and STAT5b genes respectively . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Despite intensive molecular biology investigations over the past 10 years , and an important breakthrough on how PML RARalpha , the fusion protein resulting from t ( 15 ; 17 ) , can alter RARalpha and PML functions , no definitive views on how leukemia is generated and by what mechanism ( s ) the normal phenotype is restored , are yet available . ' Resistances ' to pharmacological levels of all trans retinoic acid ( ATRA ) have been observed in experimental in vivo and in vitro models . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
RARalpha fuses to the PML gene in the vast majority of APL cases , and in a few cases to the PLZF , NPM , NuMA and STAT5b genes . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Pathways of retinoic acid or arsenic trioxide induced PML / RARalpha catabolism , role of oncogene degradation in disease remission . ^^^ Although there is evidence to suggest that PML / RARalpha expression is not the sole genetic event required for the development of acute promyelocytic leukemia ( APL ) , there is little doubt that the fusion protein plays a central role in the initiation of leukemogenesis . ^^^ This review focuses on the molecular mechanisms accounting for PML / RARalpha degradation . ^^^ Each drug targets a specific moiety of the fusion protein ( RARalpha for retinoic acid , PML for arsenic ) to the proteasome . ^^^ Specific molecular determinants ( the AF 2 transactivator domain of RARalpha for retinoic acid and the K 160 SUMO binding site in PML for arsenic ) are respectively implicated in RA or arsenic triggered catabolism . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
UBE1L is a retinoid target that triggers PML / RARalpha degradation and apoptosis in acute promyelocytic leukemia . ^^^ All trans retinoic acid ( RA ) treatment induces remissions in acute promyelocytic leukemia ( APL ) cases expressing the t ( 15 ; 17 ) product , promyelocytic leukemia ( PML ) / RA receptor alpha ( RARalpha ) . ^^^ PML / RARalpha , a repressor of RA target genes , abolished this UBE1L promoter activity . ^^^ A hallmark of retinoid response in APL is the proteasome dependent PML / RARalpha degradation . ^^^ UBE1L transfection triggered PML / RARalpha degradation , but transfection of a truncated UBE1L or E 1 did not cause this degradation . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
PML / RARalpha and FLT 3 ITD induce an APL like disease in a mouse model . ^^^ The most common fusion partner is promyelocytic leukemia protein ( PML ) , which is fused to RARalpha in the balanced reciprocal chromosomal translocation , t ( 15 ; 17 ) ( q 22 : q 11 ) . ^^^ Expression of PML / RARalpha from the cathepsin G promoter in transgenic mice causes a nonfatal myeloproliferative syndrome in all mice ; about 15 % go on to develop APL after a long latent period , suggesting that additional mutations are required for the development of APL . ^^^ Here , we test the hypothesis that PML / RARalpha can cooperate with FLT 3 ITD to induce an APL like disease in the mouse . ^^^ Retroviral transduction of FLT 3 ITD into bone marrow cells obtained from PML / RARalpha transgenic mice results in a short latency APL like disease with complete penetrance . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
In order to discover whether there is any genetic predisposition to the disease , we analyzed microsatellites flanking PML and RARalpha genes in 29 t ( 15 ; 17 ) APL patients from North Portugal and compared them with a control group of 123 healthy individuals . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The translocation of RARalpha with PML or PLZF genes in acute promyelocytic leukemia is a paradigm of the role of RARs in cancer biology . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
PML is the most frequent fusion partner of the RARalpha in the specific translocations associated with acute promyelocytic leukemia ( APL ) . ^^^ According to this idea the PML RARalpha fusion protein promotes leukemogenesis not only through repression of retinoic acid responsive genes , but also by way of interfering with several tumor suppressor proteins that cooperate to establish senescence . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Fluorescence in situ hybridization paints and RARalpha / PML cosmid probes verified that the breakpoints on chromosomes 15 and 17 were proximal to both the PML and RARalpha genes ; t ( 15 ; 17 ) ( q 13 ; 12 ) . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
PML RARalpha protein , the leukemogenic product of t ( 15 , 17 ) in acute promyelocytic leukemia , is cleaved into a truncated form termed deltaPML RARalpha during all trans retinoic acid ( ATRA ) induced differentiation of NB 4 cells . ^^^ Treatment with hexamethylene bisacetamide ( HMBA ) combined with ATRA enhances ATRA induced differentiation in ATRA insensitive NB 4 CI and arsenic resistant NB4 / As cells , and is associated with stabilization of PML RARalpha protein and increased deltaPML RARalpha formation . ^^^ Unlike forced expression of PML RARalpha , forced deltaPML RARalpha expression based on an estimated deletion of the N terminal PML portion does not repress RARE tk luc reporter activity mediated by endogenous retinoic acid receptors . ^^^ The cleavage of PML RARalpha is blocked by RARalpha antagonist Ro 41 5253 and cycloheximide and therefore requires a RARalpha transactivation dependent pathway . ^^^ Proteasome inhibitor MG 132 and caspase inhibitor Z VAD FMK do not block ATRA induced PML RARalpha cleavage and differentiation . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Nearly 98 % of cases of APL are associated with t ( 15 ; 17 ) chromosomal translocation and fusion of the PML gene to that encoding RARalpha to yield an abnormal receptor with the capability of de regulating gene expression in the haematopoietic cell , causing differentiation block and eventually the development of leukaemia . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Together these results suggest that local interruption of PML and RARalpha signaling in the skin , together with a systemic retinoid deficiency , initiates a tumor induction pathway that is independent of ras activation . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The fusion oncoprotein PML RARalpha induces endoplasmic reticulum ( ER ) associated degradation of N CoR and ER stress . ^^^ PML RARalpha , a fusion protein of promyelocytic leukemia ( PML ) and the retinoic acid receptor alpha ( RARalpha ) , causes acute promyelocytic leukemias ( APL ) . ^^^ Although the role of nuclear PML RARalpha has been extensively studied , a significant amount of PML RARalpha is in the cytoplasm . ^^^ The role cytoplasmic PML RARalpha plays in leukemogenesis is unknown . ^^^ Here we report that PML RARalpha induces the N CoR accumulation in the endoplasmic reticulum ( ER ) , leading to the induction of ER stress and the processing of activating transcription factor 6 ( ATF 6 ) , the unfolded protein response . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Improved RT PCR for detection of PML / RARalpha fusion gene in rapid diagnosis of acute promyelocytic leukemia ] . ^^^ Detection of the PML / RARalpha fusion gene by RT PCR in acute promyelocytic leukemia ( APL ) blasts is not only critical to commence promptly the specific therapy with all trans retinoic acid ( ATRA ) or arsenic trioxide ( As ( 2 ) O ( 3 ) ) , but also essential for the definition of PML breakpoint type and subsequent monitoring of minimal residual disease ( MRD ) . ^^^ The current PML / RARalpha amplification techniques with conventional nested PCR are laborious and time consuming , which fails to meet the requirements for rapid diagnosis of APL in clinical practice . ^^^ Therefore , an easily handled RT PCR methodology for the rapid and accurate amplification of PML / RARalpha fusion transcripts is needed . ^^^ A modified one round RT PCR protocol was described with a few variations which includes rapid extraction of high quality cellular total RNA , cDNA synthesis with random hexamer and M MLV reverse transcriptase , optimal concentrations of MgCl ( 2 ) ( 1 mmol / L ) , PCR primers ( 0 . 4 micro mol / L ) and Taq polymerase ( 0 . 01 U / micro l ) , hot start procedure , and concomitant amplification of PML / RARalpha fusion gene and RARalpha internal control under the identical thermocycle parameters . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
BACKGROUND : The PML gene is fused to the RARalpha gene in the vast majority of acute promyelocytic leukemias ( APL ) and has been implicated in the control of key tumor suppressive pathways . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APL ) cases expressing the t ( 15 , 17 ) product , promyelocytic leukemia ( PML ) / retinoic acid receptor alpha ( RARalpha ) , have clinical remissions through leukemic cell differentiation after all trans retinoic acid ( RA ) treatment . ^^^ We previously identified the ubiquitin activating enzyme E 1 like protein ( UBE1L ) as an RA regulated target gene in APL that triggers PML / RARalpha degradation and apoptosis . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The promyelocytic leukemia ( PML ) protein is the product of the PML gene that fuses with the retinoic acid receptor alpha ( RARalpha ) gene in acute promyelocytic leukemia ( APL ) and produces disruption of PML bodies . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia is a form of acute myelogenous leukemia , characterized by the t ( 15 ; 17 ) chromososmal translocation and the presence of the abnormal PML RARalpha fusion protein . ^^^ It is now well established that all trans retinoic acid when administered at pharmacological doses can reverse the dominant negative effects that the PML RARalpha oncoprotein exhibits on the functions of the wild type PML and RARalpha proteins . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Acute promyelocytic leukemia ( APL ) is characterized by the t ( 15 ; 17 ) ( q 22 ; q 21 ) , which results in the fusion of the promyelocytic leukemia ( PML ) gene at 15q22 with the retinoic acid alpha receptor ( RARalpha ) at 17q21 . ^^^ The 2 chimeric genes PML / RARalpha and RARalpha / PML are thought to play a role in leukemogenesis . ^^^ However , FISH analysis with a PML / RARalpha dual color kit showed a more complex translocation , resulting presumably from a two step rearrangement , with PML RARalpha fusion gene located as expected on the der ( 15 ) but the residual 5 ' RARalpha signal located on the der ( 6 ) . ^^^ This case illustrates the usefulness of combined cytogenetics , FISH , and molecular biology to evidence the PML / RARalpha fusion gene in complex cases . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The RARalpha gene on 17q12 is known to have other translocation partners than PML ( in 15q22 ) in a minority of APL cases . ^^^ The characterization of the present and other comparable APL cases with exceptional translocation partners of PML or RARalpha will help to enlighten the understanding of the pathogenesis of APL . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
In a vast majority of cases , RARalpha translocates to and fuses with the promyelocytic leukemia ( PML ) gene . ^^^ It was thought that the fusion protein PML RARalpha acts as a double dominant negative mutant to inhibit the PML and RARalpha signaling . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
This model was tested by replacing PML with dimerization domains from p50NFkappaB ( p 50 RARalpha ) or the rapamycin sensitive dimerizing peptide of FKBP 12 ( F 3 RARalpha ) . ^^^ The 10 RARalpha fusions recapitulated in vitro activities of PML RARalpha . ^^^ These results demonstrate that the dimerization interface of RARalpha fusion partners is a critical element in APL pathogenesis while pointing to other features of PML for enhancing penetrance and progression . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
All 54 patients with an AML phenotype , in whom tests for t ( 15 ; 17 ) or its fusion gene PML / RARalpha were negative , showed a speckled ( macrogranular ) nuclear pattern . ^^^ The high sensitivity and specificity of immunolabeling using PG M 3 monoclonal antibody show that it is a highly efficient and reliable tool to identify PML / RARalpha positive patients with APL and that it should be standardized as a first line diagnostic procedure . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
In the NB 4 cell line , which was derived from an APL patient and expresses PML : RARalpha , we observed a retinoic acid dependent change in the modification of specific proteins by SUMO 1 . ^^^ PML : RARalpha also stimulated hSUMO 1 conjugation in yeast . ^^^ Interestingly , however , PML and PML : RARalpha differentially complemented yeast Smt3p conjugation pathway mutants . ^^^ These findings point toward a potential function of PML and PML : RARalpha as SUMO E 3 enzymes or E 3 regulators , and suggest that fusion of RARalpha to PML may affect this activity . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
The promyelocytic leukemia retinoic acid receptor alpha ( PML RARalpha ) protein of acute promyelocytic leukemia ( APL ) is oncogenic in vivo . ^^^ It has been hypothesized that the ability of PML RARalpha to inhibit RARalpha function through PML dependent aberrant recruitment of histone deacetylases ( HDACs ) and chromatin remodeling is the key initiating event for leukemogenesis . ^^^ In parallel , we studied the in vivo leukemogenic potential of dominant negative ( DN ) and truncated RARalpha mutants , as well as that of PML RARalpha mutants that are insensitive to retinoic acid . ^^^ Comparative analysis of these TM and of TM / PML ( / ) and p 53 ( / ) compound mutants lends support to a model by which the RARalpha and PML blockade is necessary , but not sufficient , for leukemogenesis and the PML domain of the fusion protein provides unique functions that are required for leukemia initiation . . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
PML RARalpha fusion gene transcripts and biological features in acute promyelocytic leukemia patients . ^^^ The hybrid gene PML RARalpha , present in 98 % of cases , encodes a fusion protein essential to the pathogenesis of the disease . ^^^ The objective of this study was to determine the frequencies of the PML RARalpha transcripts and subtypes in a series of 32 APL patients from Northeast Brazil and to evaluate the association of these subtypes to different parameters . ^^^ The results showed the presence of PML RARalpha isoform in all patients and a higher frequency of the bcr1 / 2 subtype . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
Changing the culture pH in NB 4 cells modulated the degradation of promyelocytic leukaemia retinoic acid receptor alpha ( PML RARalpha ) , PML and RARalpha , which supported this hypothesis . ^^^
Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
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Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
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Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
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Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
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Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
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Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
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Interacting proteins: P10276 and P29590	Pubmed	SVM Score :0.0
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