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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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. The fusion transcripts could be detected in all of the 10 APL patients studied. Of the two breakpoints in the PML gene so far reported, seven APL patients had the fusion transcript compatible with the downstream (3') breakpoint, and the other three APL patients were considered to have the upstream (5') breakpoint. RT-PCR could detect the fusion transcripts from as little as 50 pg bone marrow RNA, and from as little as 0.5 pg bone marrow RNA with the nested PCR. 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. This system could be useful to detect minimal residual leukemia cells and accordingly modify the treatment strategy, as well as to make a quick diagnosis with a small amount of clinical sample.
Leukemia 1993 Apr
PMID:Reverse transcription-polymerase chain reaction for PML-RAR alpha fusion transcripts in acute promyelocytic leukemia and its application to minimal residual leukemia detection. 838 49

The chromosome breakpoints of the acute promyelocytic leukemia (APL)-specific 15;17 translocation have recently been isolated. 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. Both are expressed in APL. 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. Experiments to investigate the biological activity of the abnormal translocation products are in progress. 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. However, there is accumulating evidence that it acts by interfering with normal endogenous pathways of both RAR alpha and PML. The RAR alpha receptor is implicated in regulating the myeloid differentiation induced by RA. Although the physiological function of PML is not known, it is probably a transcription factor. Definition of the molecular architecture of the t(15;17) has furnished further tools for: (1) molecular diagnosis of APL and (2) highly sensitive evaluation of the neoplastic clone during antileukaemic therapy. The molecular identification of residual APL disease after anti-leukaemia therapy allows patients at risk of relapse to be identified.
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PMID:The molecular genetics of acute promyelocytic leukemia. 839 81

Acute promyelocytic leukaemia (APL) is a distinct subtype of acute myeloid leukaemia distinguished by the presence of a balanced chromosomal translocation: t(15; 17). The most characteristic clinical manifestation of this disease is the presence of a haemorrhagic syndrome associated with an abnormal coagulation profile. In the last few years significant progress in the understanding of the biology of this leukaemia and its treatment has been done. 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. In contrast to the other acute myeloid leukaemia subtypes APL shows high response rate to induction monochemotherapy with anthracycline drugs and with all-trans retinoic acid.
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PMID:[Progress in biology and the treatment of acute promyelocytic leukemia]. 848 32

We have screened mutations of the N-ras gene at codons 12, 13, and 61 in leukemia cells obtained from 100 patients with acute myeloid leukemia (AML), and found mutated N-ras alleles in 9 patients. We further analyzed the polyclonality of multiple N-ras gene mutations in 4 AML patients. One patient, who had the monoclonal karyotype, t(11;17), had two types of double missense mutations at codons 13 and 61 in the same allele. 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. We have demonstrated that multiple clonality of the N-ras gene is occasionally observed in leukemia with a monoclonal karyotype. These findings indicate that the N-ras mutations may not always be characterized simply by an accumulative process and that the activated N-ras gene alone is not sufficient to cause leukemia.
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PMID:Clonal analysis of multiple point mutations in the N-ras gene in patients with acute myeloid leukemia. 851 4

PML is a nuclear matrix protein with growth suppressing properties, whose expression is deregulated during oncogenesis. 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. Here we show that interferons (IFNs) alpha, beta, and gamma upregulate PML mRNA expression. Analysis of 5' genomic sequences of the PML gene revealed an IFN-alpha/-beta stimulated response element (ISRE) and an IFN-gamma activation site (GAS) in the untranslated first exon. Binding of IFN signal transducers and activators of transcription (STATs) was demonstrated to be weak for the PML GAS, but strong for the PML ISRE which also seemed to contribute substantially to the IFN-gamma response. Thus, PML is a primary target gene of IFNs and would appear as a suitable candidate for mediating some of their antiproliferative effects. Abnormalities of PML structure, localisation or expression in human malignancy, constitute examples of how an IFN target gene may be altered in oncogenesis.
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PMID:Transcriptional induction of the PML growth suppressor gene by interferons is mediated through an ISRE and a GAS element. 854 13

RT-PCR assays used to detect acute promyelocytic leukemia (APL) are generally considered less sensitive than those for other hematological malignancies, such as CGL. 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. Therefore, we have evaluated both assays in parallel to monitor a group of 12 de novo APL patients who relapsed despite treatment with both all-trans retinoic acid (ATRA) and chemotherapy. 5' (bcr 3) breakpoints in PML were over represented among the group and three patients had complex cytogenetic abnormalities suggesting both factors may increase the risk of relapse. 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. Whether the duration of PCR positivity is a helpful prognostic indicator in those patients who ultimately become PCR negative is being addressed by
Leukemia 1996 Jan
PMID: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. 855 40

Myeloblastin (mbn) is a serine protease involved in the control of growth and differentiation of human leukemic cells. In the promyelocytic-like human leukemia cell line HL-60 this protease is inhibited during retinoic acid (RA) induced differentiation. 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. We have shown that while mbn was early down-regulated in HL60 cells treated with all trans RA, the inhibition of this gene was considerably delayed in NB4 cells, which carry the t(15;17) translocation, upon treatment with the same inducer. This observation suggested that the changes in the myeloblastin regulation by RA found in NB4 cells could be ascribed to the presence of the fusion protein PML-RAR. To verify this hypothesis we have cloned the putative promoter region of mbn gene. Transactivation properties of endogenous retinoic acid receptors on this region have been tested in transfection experiments of HL60 and NB4 cell lines before and after treatment with all trans RA. We found that RA induced a significant inhibition of the luciferase reporter gene in HL60 cells. In contrast, a strong stimulation of luciferase activity was observed in NB4 cells treated with RA. The analysis of the promoter region allowed us to identify a new response element for retinoic acid receptors, named mREpal, which is probably affected by the product of t(15;17) translocation.
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PMID:[Effect of translocation t(15;17) on the gene expression regulation of myeloblastin during all trans retinoic acid induced myeloid differentiation in human leukemic cells]. 856 66

PML has been identified through its fusion to the RAR alpha gene in acute promyelocytic leukemia (APL). The PML protein is specifically associated to nuclear bodies (NBs) whose alterations in APL were proposed to contribute to leukemogenesis. The role of this nuclear domain (which also harbors the Sp100 autoantigen and the NDP52 protein) is unknown. Here, we show that the PML protein, like Sp100 and NDP52, is induced by interferons (IFNs alpha, beta and gamma) in a large variety of human cells. Interestingly, the NBs that contain the three IFN-induced proteins appear to be associated to speckles labelled by the IFN-mediator Mx1. These observations link NBs to IFN response pathways, which may contribute to the elucidation of the biological role of these structures. 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. As PML has growth suppressing properties, it may mediate some of the antiproliferative effects of IFN. In APL, inactivation of PML may result in disruption of growth control.
Leukemia 1995 Dec
PMID:Induction of the PML protein by interferons in normal and APL cells. 860 13

Translocation t(15;17)(q22;q21) is an acquired clonal cytogenetic change present in almost all cases of acute promelocytic leukemia (APL). The molecular genetic basis of the translocation supports its integral role in pathogenesis. We describe a patient with APL in whom the leukaemic clone was characterized by a true variant of the classical t(15;17). The patient whose disease had numerous atypical clinical features, had t(11;17)(q13;121). 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. These data, along with previous reports of rare variant translocations in APL, indicate that while dysregulation of RARA by gene fusion may be essential for the APL phenotype, the particular fusion partner may determine clinicopathological aspects, including presentation, response to treatment with all-trans retinoic acid (ATRA), and prognosis. 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. Investigation of these factors promises to shed light on the complex development pathways involved in the regulation of haematopoiesis.
Leukemia 1996 Apr
PMID:A new variant translocation in acute promyelocytic leukaemia: molecular characterization and clinical correlation. 861 56

Reverse transcriptase-polymerase chain reaction is a recent technique in the diagnosis and assessment of minimal residual disease of acute promyelocytic leukemia, by amplification, of the different PML-RARalpha transcripts resulting from the t(15;17) translocation. The main issues addressed by the Second Workshop on PML-RARalpha-RT-PCR which took place in Paris, France on 17-18 December 1994, were related to (1) defining the specific pitfalls of the PML-RARalpha-RT-PCR, and means to improve the sensitivity of the technique; (2) the validity of PCR results obtained in CR to provide information on the extent of the disease; (3) the frequency and prognostic value of the different PML-RARalpha transcripts.
Leukemia 1996 Feb
PMID:RT-PCR in acute promyelocytic leukemia: second workshop of the European Retinoic Group, Paris, France, 17-18 December 1994. 863 50


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