Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute promyelocytic leukaemia (APL) associated with a t(15;17) translocation generates a PML/RAR alpha chimaeric gene which is transcribed as a fusion PML/RAR alpha mRNA. To clarify the pathophysiologic role of PML/RAR alpha in APL patients, we examined the expression of PML/RAR alpha in haemopoietic colonies in five patients with APL by reverse transcriptase polymerase chain reaction (RT-PCR) analysis. By the two-step RT-PCR method, we demonstrated that PML/RAR alpha positive clones were present in progenitor cells including both CFU-GM and BFU-E in two cases. This result suggests that the translocation of PML/RAR alpha occurred in a pluripotent stem cell in some APL patients. In four patients we detected two amplified cDNA fragments of 780 and 640 bp which presumably arose by alternative splicing of the PML gene. Interestingly, of CFU-GM and BFU-E colonies examined in four patients, there were three different types of colonies: those expressing only the 780 bp fragment, those expressing only the 640 bp fragment, and those expressing both fragments. This suggests that alternative splicing was clonally determined in each colony. We describe a useful RT-PCR technique for the study of gene expression in a limited number of haemopoietic precursor cells.
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PMID:PML/RAR alpha fusion gene is expressed in both granuloid/macrophage and erythroid colonies in acute promyelocytic leukaemia. 813 68

Acute promyelocytic leukemia (APL) is a rare subtype of acute myelogenous leukemia. It is frequently associated with a life-threatening hemorrhagic diathesis, often aggravated by induction cytotoxic chemotherapy. Patients with APL have bone marrow infiltration by abnormal promyelocytes, usually with prominent cytoplasmic granulation. These patients have a unique cytogenetic abnormality, a balanced reciprocal translocation between the long arms of chromosomes 15 and 17. 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. This assay is extremely useful in the diagnosis and detection of minimal residual disease in APL patients. All trans-retinoic acid (ATR) differentiates the malignant cell clone and corrects the coagulopathy associated with this disease. The most important adverse effect is a respiratory distress syndrome, treatable with steroids, if detected at its onset. ATR yields durable remissions in patients with APL, after consolidation with cytotoxic chemotherapy.
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PMID:[Acute promyelocytic leukemia. The therapeutic advances]. 828 19

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. Therefore, amplification of the breakpoints region by polymerase chain reaction (PCR) with genomic DNA has been considered to be difficult. In the present study, a method was developed to detect the 15;17 translocation with genomic DNA. Of 13 patients with APL, four were detected to have the rearrangement of genomic DNA. At present, reverse transcriptase-polymerase chain reaction analysis is one of the methods available for diagnosis and detection of the residual leukemic cells in APL. 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. Furthermore, this method is applicable to patients for whom RNA samples of the leukemic cells are not available.
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PMID:Detection of PML/retinoic acid receptor a gene rearrangements by polymerase chain reaction using genomic DNA in patients with acute promyelocytic leukemia. 838 82

Acute promyelocytic leukemia (APL) is characterized cytogenetically by the t(15;17)(q22;q11-21) translocation. 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). Breakpoint usage in PML was determined using a combination of PCR amplification with differing 5' primers, junction-specific probes, and sequence analysis in selected cases. 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. Transcripts resulting from breakpoints in bcr1 were detected in 59 percent of cases, bcr2 in 27 percent and bcr3 in 14 percent. This distribution is dissimilar to that observed in adults, where bcr2 comprises a lesser and bcr3 a greater portion of cases. These results suggest that the pathogenesis of the t(15;17) in APL may differ among patient sets. RT-PCR with these primer sets is a reliable method for detecting PML/RAR alpha chimeric transcript in t(15; 17)-containing APL.
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PMID:Molecular analysis of the PML/RAR alpha chimeric gene in pediatric acute promyelocytic leukemia. 870 34

We studied the quantitative changes in PML/retinoic acid receptor alpha (PML/RAR alpha) fusion mRNA using the reverse transcriptase-polymerase chain reaction (RT-PCR) and the in vitro differentiation of leukemic cells from eight acute promyelocytic leukemia (APL) patients during treatment with all-trans retinoic acid (ATRA). In three patients, the intensity of the chimeric PML/RAR alpha bands decreased rapidly after the start of ATRA therapy. However, these three patients required variable periods of time to obtain complete remission (CR) (24, 29 and 100 days). In the five other patients, the chimeric bands decreased slowly, and the time until CR also varied (22, 28, 30, 39 and 67 days). As for the in vitro assay, leukemic cells from the three patients who achieved CR in a short period of time (22, 28 and 30 days) showed marked differentiation in response to 1 mumol/L ATRA, and leukemic cells from the four patients with slow or delayed clinical responses to ATRA did not show morphological differentiation in vitro. These findings suggest that the clinical response of APL patients to ATRA is predicted from the results of the in vitro differentiation assay, but not by RT-PCR analysis of the PML/RAR alpha fusion mRNA.
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PMID:Evaluation of semiquantitative reverse transcriptase-polymerase chain reaction assay of PML/retinoic acid receptor alpha mRNA and in vitro differentiation assay as prognostic prediction in acute promyelocytic leukemia treated with all-trans retinoic acid. 881 May 54

Six patients with acute promyelocytic leukaemia (APL) and t(15;17) were investigated by cytogenetics and by reverse transcriptase polymerase chain reaction (RT-PCR) for the fusion transcript PML-RARA. The clone was detected in remission following all-trans retinoic acid and chemotherapy by cytogenetics and/or by RT-PCR up to 2 months from diagnosis. Thereafter the PML-RARA transcript was not seen in 20/21 first remission samples in five cases studied. Remission was maintained in two patients, one following bone marrow transplantation (BMT). Despite serial negative RT-PCR results, PML-RARA reemerged at or prior to relapse following BMT in the remaining three cases. Frequent molecular monitoring and caution in the interpretation of negative RT-PCR results are indicated in APL.
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PMID:Relapse of acute promyelocytic leukemia follows serial negative RT-PCR assays: a cautionary tale. 894 82

We treated two children with acute promyelocytic leukemia (APL) in whom complete remission was successfully induced by oral administration of all-trans retinoic acid (ATRA). We followed these patients with conventional chemotherapy. The first patient has remained in continuous complete remission. However, the other patient relapsed during the maintenance therapy and died of progressive disease in spite of a second treatment with ATRA and chemotherapy. From a clinical point of view, the latter case had a hyperleukocytosis on admission. Also morphologically speaking, this patient had a different M3 variant than the first case. There are two major isoforms of PML/RAR alpha transcripts, so called short and long type transcripts, according to the breakpoints in the PML genes. In the first case the "long type' isoform was detected by reverse transcriptase polymerase chain reaction (RT/PCR) amplification. On the other hand the "short type' isoform was observed in the latter case. Also the second case became PCR positive at relapse, although the detectable isoform was negative during remission. The "short type' isoform may be related to the poor prognosis and RT/PCR analyses may be a powerful to detect early relapse.
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PMID:[Childhood acute promyelocytic leukemia treated with all-trans retinoic acid]. 899 31

Two patients with relapsed acute promyelocytic leukaemia previously treated with all-trans retinoic acid (ATRA), were treated with a new synthetic retinoid, Am-80. In both patients pancytopenia gradually resolved without an increase in leukaemic cells, and differentiation of leukaemic cells was observed morphologically in bone marrow. Without the use of anti-leukaemic agents, both cases achieved complete remission (CR) on days 52 and 38 of treatment, respectively. On the day of CR, PML gene rearrangement and the t(15;17) translocation disappeared, though PML-RAR alpha chimaeric messenger RNA was still detected by reverse transcriptase polymerase chain reaction. Both patients then received conventional chemotherapy for consolidation of CR. These clinical experiences suggest that Am-80 may be an active agent for APL patients who have relapsed from ATRA-induced remission.
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PMID:Re-induction of complete remission with a new synthetic retinoid, Am-80, for relapse of acute promyelocytic leukaemia previously treated with all-trans retinoic acid. 913 55

Acute promyelocytic leukemia (APL) is typified by the reciprocal translocation, t(15; 17)(q22; q21), leading to the formation of PML-RARalpha and RARalpha-PML fusion genes. We have characterized 7 cases of morphologic APL found to lack the t(15; 17) on conventional cytogenetic assessment. 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)(q23; q12-21), 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. Immunofluorescence studies were performed using antibodies raised against PML and PIC 1, a ubiquitin-homology domain protein previously identified as an interaction partner of PML. In acute myeloid leukemia (AML) of subtypes other than M3, PIC 1 was localized to the nuclear membrane and colocalized with PML within discrete nuclear bodies. 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. Although deregulation of the putative growth suppressor PML and delocalization of other nuclear body constituents have been advocated to play a key role in the development of t(15; 17)-associated APL, the present study shows that disruption of PML nuclear bodies per se is not a prerequisite for the pathogenesis of APL.
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PMID:Characterization of cryptic rearrangements and variant translocations in acute promyelocytic leukemia. 938 4

Although the majority of patients with acute promyelocytic leukemia (APL) are potentially cured by treatments combining all-trans retinoic acid (ATRA) and chemotherapy (CHT), a sizable proportion (around 30%) will relapse during follow-up. Retrospective molecular monitoring studies using reverse transcriptase-polymerase chain reaction (RT-PCR) for the specific PML/RARalpha fusion gene, have shown that a positive test usually precedes the occurrence of hematologic relapse. Prospective RT-PCR analyses were performed since 1993 at diagnosis and at preestablished time intervals during follow-up in bone marrow (BM) samples of 163 patients with PML/RARalpha+ APL enrolled in the multicenter Gruppo Italiano Malattie Ematologiche Maligne dell' Adulto (GIMEMA) trial AIDA (All-trans retinoic acid plus Idarubicin). Treatment consisted of ATRA and idarubicin for induction followed by three polychemotherapy courses as consolidation. The sensitivity level of the RT-PCR assay for PML/RARalpha, as assessed by serial dilution experiments, was 10(-4). All patients were in hematologic remission and tested PCR- at the end of consolidation. Of 21 who converted to PCR-positive thereafter, 20 underwent hematologic relapse at a median time of 3 months (range, 1 to 14) from the first PCR+ result. Seventeen of these 21 (81%) PCR+ conversions were recorded within the first 6 months postconsolidation. Of 142 who tested persistently PCR- in >/=2 tests after consolidation, 8 had hematologic relapse and 134 remained in complete remission (CR) after a median follow-up of 18 months (range, 6 to 38) postconsolidation. Using a time-dependent Cox model, the relative risk of hematologic relapse of patients who converted to PCR+ was 31.8 (confidence limits 95%, 12.9 to 78.3). Our results indicate that conversion to PCR positivity for PML/RARalpha during remission is highly predictive of subsequent hematologic relapse and highlight the prognostic value of stringent molecular monitoring during the early postconsolidation phase in APL. As a result of the present study, salvage treatment in patients enrolled in the GIMEMA trial AIDA is now anticipated at the time of molecular relapse, defined as the conversion to PCR positivity in two successive BM samplings during follow-up.
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PMID:Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RARalpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter "AIDA" trial. GIMEMA-AIEOP Multicenter "AIDA" Trial. 968 Mar 45


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