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)

Telomere length maintenance is essential for cellular immortalization, and thus tumorigenesis. Most human tumors and immortal cell lines maintain their telomeric DNA via the activity of a specialized reverse transcriptase, telomerase. Stabilization of telomeric repeat tracts may also be achieved through a telomerase-independent mechanism, referred to as alternative lengthening of telomeres (ALT). ALT cells are telomerase negative and are characterized by extremely long and heterogeneously sized telomeres and novel multiprotein structures called ALT-associated PML nuclear bodies which are unique to ALT cells. To determine if reconstitution of telomerase activity suppressed ALT and restored wild-type telomere lengths, we introduced the catalytic subunit of telomerase into two ALT cell lines. Initially, two clonal lines exhibited enrichment of shorter telomeres while maintaining a population of ultra-long telomeres similar to that observed in the parental line, suggesting that telomerase is stabilizing the shorter telomeres in the population. Telomere length in the third clonal line was not detectably different from that in the parental cell line. One clonal line with a phenotype of shorter telomeres maintained this pattern over time in culture while the second gradually reverted to the parental ALT telomere length pattern, concurrent with reduction of telomerase activity. All clones continued to maintain ALT-associated PML nuclear bodies regardless of whether telomerase was present. The data suggest that introduction of telomerase activity alone is not sufficient to completely repress ALT, that telomerase acts preferentially on the shortest telomeres in the culture and that the ALT and telomerase pathways may be present concurrently in mammalian cells.
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PMID:Effects of reconstitution of telomerase activity on telomere maintenance by the alternative lengthening of telomeres (ALT) pathway. 1155 32

PCR-based monitoring of minimal residual disease (MRD) in acute leukemias can be achieved via detection of fusion gene transcripts of chromosome aberrations or detection of immunoglobulin (Ig) and T cell receptor (TCR) gene rearrangements. We wished to assess whether both PCR targets are complementary in acute myeloid leukemia (AML). We investigated 105 consecutive AML cases for the presence of fusion gene transcripts by reverse transcriptase polymerase chain reaction (RT-PCR): AML1-ETO associated with t(8;21), CBFB-MYH11 with inv(16), PML-RARA with t(15;17), BCR-ABL with t(9;22), and MLL-AF4 with t(4;11). In 17 out of 105 AML cases (16%), fusion gene transcripts were found. Ninety-five of these AML patients (13 with fusion gene transcripts) were also investigated for the presence of IGH, IGK, TCRG and TCRD rearrangements by Southern blot and/or PCR heteroduplex analysis and sequencing. In nine out of 95 patients (9.5%), such rearrangements were found. Combined data revealed that only one patient with a fusion gene transcript had a coexistent Ig/TCR rearrangement. The nine AML patients with Ig/TCR rearrangements, as well as five additional AML patients from a previous study were investigated in more detail, revealing that Ig/TCR rearrangements in AML are immature and unusual. The presence of Ig/TCR rearrangements in AML did not correlate with RAG gene expression levels as determined by real-time quantitative PCR. In conclusion, fusion gene transcripts and Ig/TCR rearrangements are infrequent, but complementary MRD-PCR targets in AML.
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PMID:Fusion gene transcripts and Ig/TCR gene rearrangements are complementary but infrequent targets for PCR-based detection of minimal residual disease in acute myeloid leukemia. 1189 40

Acute promyelocytic leukaemia (APL) is characterized by the t(15;17)(q22;q21) leading to the formation of PML-RARalpha and RARalpha-PML fusion genes which provide suitable targets for the assessment of minimal residual disease (MRD). Studies have focused upon detection of PML-RARalpha because, although assays for RARalpha-PML transcripts are more sensitive, they are not applicable to 25% of cases. Among patients receiving standard therapy (ATRA and anthracycline-based chemotherapy), qualitative assays using a nested reverse transcriptase-polymerase chain reaction (RT-PCR), which typically achieve sensitivities of 1 in 10(4), have been found to provide independent prognostic information suitable for directing an approach to treatment. Detection of PML-RARalpha at the end of consolidation, or subsequent recurrence of PCR positivity, heralds relapse, which may, however, be averted by additional therapy leading to improvements in survival for this "high-risk" subgroup of patients. MRD analysis has also proved of value in predicting response to autologous transplant procedures undertaken in second complete remission and in directing the need for additional therapy in the post-transplantation setting. Overall, these studies undertaken within the context of a relatively homogeneous disease entity confirm that MRD monitoring provides independent prognostic information, serving as a valuable model for improving treatment strategy in other molecularly defined subsets of acute myeloid leukaemia (AML). Nevertheless, conventional nested RT-PCR assays fail to detect residual disease in a significant proportion of patients who ultimately relapse, which may be a reflection of RNA quality and/or assay sensitivity. Therefore, it is hoped that "real-time" quantitative RT-PCR technology (RQ-PCR) which permits quantification of fusion gene transcripts in relation to endogenous control genes will be even more predictive of outcome and achieve greater standardization of MRD detection in the context of large-scale clinical trials.
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PMID:The significance of minimal residual disease in patients with t(15;17). 1198 21

Postmortem neuropathologic reports for a consecutive series of 436 HIV-seropositive patients who died between 1985 and 1999 were matched with clinical data for 371 of them. Cases were divided into four groups depending on the date of death. The chosen time periods reflected the type of antiretroviral therapy available: before 1987 (before zidovudine); 1987-1992, the period of monotherapy (nucleoside analog reverse transcriptase inhibitors [NRTIs]); 1993-1995, the era of the use of dual NRTI combinations; and 1996-1999, the era of highly active antiretroviral therapy (HAART) containing protease inhibitors. Fifty-seven percent of our cases in this group had been prescribed HAART. In our study population, accessibility to the latest antiretroviral therapy was widespread. The total number of HIV autopsies declined after the advent of combination therapy. The prevalence of opportunistic infections-cytomegalovirus, toxoplasmosis, cryptococcosis, and central nervous system lymphoma-decreased over time. Cerebral tuberculosis, aspergillosis, herpes, and progressive multifocal leukoencephalopathy showed a downward trend, but the numbers were too low for statistical analyses. The incidence of HIV encephalopathy increased over time (p =.014). The rising prevalence of HIV encephalopathy at time of death may reflect a longer survival time after initial HIV infection in the HAART era. Although combination therapies decrease overall mortality and prevalence of CNS opportunistic infections, these therapies may be less active in preventing direct HIV-1 effects on the brain.
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PMID:HIV-related neuropathology, 1985 to 1999: rising prevalence of HIV encephalopathy in the era of highly active antiretroviral therapy. 1239 95

The WT1 gene encoding a zinc finger DNA-binding protein was identified as a tumor suppressor gene being responsible for Wilms' tumor. Recently, aberrant expression of WT1 gene and an inverse correlation between its expression levels and prognosis have been demonstrated in acute myeloid leukemia (AML), suggesting it is a novel tumor marker for leukemic blast cells. To explore whether the WT1 may be used as a marker for detection of minimal residual disease (MRD) in acute leukemia, we examined the sensitivity of the nested reverse transcriptase-polymerase chain reaction (RT-PCR) by using WT1 gene primers in comparison with tumor-specific marker genes, such as PML/RARalpha gene in NB4 cells or bcr-abl gene in K562 cells. In all samples, the integrity of RNA was confirmed by amplification of the c-abl gene as an internal control. The limits in amount of leukemic cells detected by two-step RT-PCR with primers for WT1 or tumor specific fusion gene were 10(-4) and 10(-5) in NB4 cells and 10(-3) to 10(-4) and higher than 10(-6) for K562 cells, respectively. None was WT1 positive in peripheral blood mononuclear cells (MNC) from 29 blood donors, while bone marrow MNCs from eight of 21 cases (38.1%) of nonmalignant patient WT1 gene expression were found. Our results suggested that monitoring of WT1 expression makes it possible to rapidly assess the effectiveness of treatment and follow up MRD in AML cases regardless of the presence or absence of tumor-specific markers.
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PMID:[Expression of the Wilms' Tumor Gene WT1 and Detection of Minimal Residual Disease in Acute Leukemia] 1257 85

Rapid progress in the development of highly active antiretroviral therapy has changed the observed patterns in HIV encephalitis and AIDS-related CNS opportunistic infections. Early in the AIDS epidemic, autopsy studies pointed to a high prevalence of these conditions. With the advent of nucleoside reverse transcriptase inhibitors, the prevalence at autopsy of opportunistic infections, such as toxoplasmosis and progressive multifocal leukoencephalopathy, declined while that of HIV encephalitis increased. After the introduction of protease inhibitors, a decline in both HIV encephalitis and CNS opportunistic infections was observed. However, with the increasing resistance of HIV strains to antiretrovirals, there has been a resurgence in the frequency of HIV encephalitis and HIV leukoencephalopathy. HIV leukoencephalopathy in AIDS patients failing highly active antiretroviral therapy is characterized by massive infiltration of HIV infected monocytes/macrophages into the brain and extensive white matter destruction. This condition may be attributable to interactions of anti-retrovirals with cerebrovascular endothelium, astroglial cells and white matter of the brain. These interactions may lead to cerebral ischemia, increased blood-brain barrier permeability and demyelination. Potential mechanisms of such interactions include alterations in host cell signaling that may result in trophic factor dysregulation and mitochondrial injury. We conclude that despite the initial success of combined anti-retroviral therapy, more severe forms of HIV encephalitis appear to be emerging as the epidemic matures. Factors that may contribute to this worsening include the prolonged survival of HIV-infected patients, thereby prolonging the brain's exposure to HIV virions and proteins, the use of increasingly toxic combinations of poorly penetrating drugs in highly antiretroviral-experienced AIDS patients, and selection of more virulent HIV strains with higher replication rates and greater virulence in neural tissues.
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PMID:Changing patterns in the neuropathogenesis of HIV during the HAART era. 1274 73

Acute promyelocytic leukaemia (APL) is characterized by a unique genetic marker in virtually 100% of cases, i.e. the PML/RARalpha fusion gene which is readily amplified by the reverse transcriptase-polymerase chain reaction (RT-PCR) method. Several international groups reported the prognostic significance of minimal residual disease (MRD) assessment in APL, indicating that sequential PCR analysis should be used as a guide to therapy. In fact, such evaluation offers the possibility of identifying, after front-line treatment, either patients requiring additional therapy or patients at low risk who are presumably cured and who may be spared unnecessary toxicity. In this view, the terms molecular remission and molecular relapse are now widely employed to define a more advanced therapeutic objective and a condition necessitating anticipated salvage, respectively. The introduction of quantitative PCR through automated technologies is likely to further improve standardization of the method and comparison of results obtained in the context of large clinical trials.
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PMID:The importance of molecular monitoring in acute promyelocytic leukaemia. 1293 66

In all, 17 consecutive patients in hematological complete remission (HCR) of acute promyelocytic leukemia (APL) received allogeneic stem cell transplantation (SCT) from an HLA-identical sibling and were monitored by reverse transcriptase polymerase chain reaction of PML/RARalpha prior and after transplant. Median age was 31 years (range 3-50 years). At 10 years, the actuarial probabilities of nonrelapse mortality, relapse and disease-free survival were 32% (95% CI: 8-56%), 33% (95% CI: 6-60%) and 46% (95% CI: 22-70%). Six patients tested PCR +ve (1st HCR n=2; 2nd HCR n=3; 3rd HCR n=1) and 11 PCR -ve (2nd HCR n=11) pre-SCT. Of the six patients PCR +ve, two showed early persistence of PCR positivity and converted to sustained PCR negativity after CSA withdrawal (one died of secondary tumor in molecular remission and one is alive in relapse), while four converted to PCR -ve rapidly (one died of the underlying disease and three are in molecular remission). Of the 11 patients PCR -ve pre-SCT, six died (four of transplant-related mortality, one of relapse and one after heart transplantation) and five are alive, four in molecular remission and one is in relapse. Allogeneic SCT seems a valid option for advanced APL, particularly for the poor prognostic group of patients with pre-SCT molecularly persistent disease.
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PMID:Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia: results in patients treated in second molecular remission or with molecularly persistent disease. 1451 40

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. The results in 40 patients with newly diagnosed APL showed that the improved RT-PCR protocol allowed the rapid detection of PML/RARalpha fusion gene and the accurate discrimination of its transcript types, and simultaneous amplification of RARalpha internal control under the identical program in less than 6 hours. There were no false positive or negative results found with the assay. In conclusion, the assay reported here is proved to be a simple, easily handled, and highly specific procedure for the diagnosis of APL cases, particularly those requiring such urgent therapeutic intervention as ATRA or As(2)O(3) and meriting its further application in APL management.
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PMID:[Improved RT-PCR for detection of PML/RARalpha fusion gene in rapid diagnosis of acute promyelocytic leukemia]. 1470 40

We studied the immunophenotype of 100 cases of acute promyelocytic leukemia (APL) with cytogenetic evidence of t(15;17)(q22;q21), 72 hypergranular (M3) and 28 microgranular (M3v), and correlated the results with molecular and clinical features. Most neoplasms (75/100 [75%]) had a typical immunophenotype: CD13+CD33+CD34-HLA-DR-. CD64, CD2, CD34, and HLA-DR were expressed in 27% (24/88), 23% (22/94), 21% (21/100), and 9% (9/98), respectively. CD34 expression was restricted to M3v; HLA-DR and CD2 were expressed more often in M3v than in M3 (P < .001). PML-RARalpha fusion transcripts were detected by reverse transcriptase-polymerase chain reaction in all 70 patients assessed. The short form of PML-RARalpha transcripts was found more frequently in M3v (P < .002) and CD2+ APL (P < .0001) than in M3 and CD2- APL, respectively. The median follow-up was 128 weeks. CD2+ APL was associated significantly with leukocytosis (P = .004), shorter complete remission duration (P = .03), and a trend toward shorter overall survival (P = .07) than CD2- APL. Overall survival for M3v vs M3 (P = .68) and short vs long transcripts (P = .21) was not significantly different. Immunophenotyping is useful for predicting the biologic and clinical behavior of APL.
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PMID:Expression of CD2 in acute promyelocytic leukemia correlates with short form of PML-RARalpha transcripts and poorer prognosis. 1502 45


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