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:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The success of tyrosine kinase inhibition of the BCR-ABL fusion gene with imatinib in the treatment of chronic myeloid leukemia (CML) has resulted in the use of molecular detection techniques for routine clinical management. Current clinical guidelines recommend the use of molecular testing of BCR-ABL transcript levels by quantitative real-time transcriptase polymerase chain reaction (qRT-PCR) every 3 to 6 months. However, qRT-PCR methods have not yet been standardized, particularly in the United States, where most patients are initially treated outside of academic practices. The lack of standard methods for molecular monitoring has resulted in the failure to follow National Comprehensive Cancer Network and European LeukemiaNet guideline recommendations and in the misinterpretation of test results. Standardization of molecular monitoring methods and adherence to guideline recommendations are important for optimal patient management. In this article, we provide an update on the current clinical trial results by using the molecular technique to monitor patient response. Current problems and efforts in standardizing the qRT-PCR technique and reporting are reviewed. We provide examples of potential problems of various reference laboratory reports and present recommendations for assessing molecular test results. These recommendations seem particularly important because nilotinib and dasatinib appear to have improved the molecular response in the initial treatment of CML.
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PMID:Translating trial-based molecular monitoring into clinical practice: importance of international standards and practical considerations for community practitioners. 2172 5

Molecular monitoring of BCR-ABL transcript levels by real-time quantitative PCR is increasingly being used to diagnose the disease and assess treatment response in patients with chronic myeloid leukemia (CML). This has become particularly relevant when residual levels of leukemia usually fall below the level of detection by cytogenetic analysis. Forty-two CML patients, including 18 males (42.86%) and 24 females (57.14%) aged 7-75 years, were enlisted for the study and followed-up for the response to imatinib treatment. Patients were subjected to Multiplex RT-PCR (reverse-transcriptase PCR) and were all found to harbor either e13a2 or the e14a2, which could be analyzed by a single Taqman probe based quantitation kit (Geno-Sen's) to quantitate the BCR-ABL transcript load. The Multiplex RT-PCR and peripheral blood cytogenetics providing specific and sensitive detection of BCR-ABL fusion transcripts and metaphase signal load respectively were used as parallel reference tools to authenticate the q-PCR findings. There was 100% concordance between the multiplex RT-PCR and the q-PCR as every positive RT-PCR assay for a transcript reflected as q-PCR load of above 0% for that transcript. q-PCR also demonstrated a strong Pearson correlation with the cytogenetic response.
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PMID:Real-time quantitative PCR: a reliable molecular diagnostic and follow-up tool for 'minimal residual disease' assessment in chronic myeloid leukemia. 3005 31

Drug resistance to TKIs and the existance of CML leukemia stem cells is an urgent problem. In this study, we demonstrate that quinacrine (QC) induces apoptosis in BCR-ABL positive CML and acute lymphoblastic leukemia (ALL) cells. Interestingly, QC inhibits the colony formation of primary CD34⁺ progenitor/stem leukemia cells from CML patients. QC targets RNA polymerase I, which produces ribosomal (r)RNA, involving in protein translation process. Also, QC treatment prolongs CML-like mice survival and inhibits K562 tumor growth in vivo. In conclusion, we demonstrate that QC depletes BCR-ABL protein and suppresses Ph-positive leukemia cells in vitro and in vivo.
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PMID:Quinacrine Depletes BCR-ABL and Suppresses Ph-Positive Leukemia Cells. 3129 70

To elucidate dynamic changes in native BCR-ABL and alternatively spliced tyrosine kinase inhibitor (TKI)-resistant but function-dead BCR-ABL^Ins35bp variant, following commencement or discontinuation of TKI therapy, each transcript was serially quantified in patients with chronic myeloid leukemia (CML) by deep sequencing. Because both transcripts were amplified together using conventional PCR system for measuring International Scale (IS), deep sequencing method was used for quantifying such BCR-ABL variants. At the initial diagnosis, 7 of 9 patients presented a small fraction of cells possessing BCR-ABL^Ins35bp , accounting for 0.8% of the total IS BCR-ABL, corresponding to actual BCR-ABL^Ins35bp value of 1.1539% IS. TKI rapidly decreased native BCR-ABL but not BCR-ABL^Ins35bp , leading to the initial increase in the proportion of BCR-ABL^Ins35bp . Thereafter, both native BCR-ABL and BCR-ABL^Ins35bp gradually decreased in the course of TKI treatment, whereas small populations positive for TKI-resistant BCR-ABL^Ins35bp continued fluctuating at low levels, possibly underestimating the molecular response (MR). Following TKI discontinuation, sequencing analysis of 54 patients revealed a rapid relapse, apparently derived from native BCR-ABL⁺ clones. However, IS fluctuating at low levels around MR4.0 marked a predominant persistence of cells expressing function-dead BCR-ABL^Ins35bp , suggesting that TKI resumption was unnecessary. We clarified the possible mechanism underlying mis-splicing BCR-ABL^Ins35bp , occurring at the particular pseudo-splice site within intron8, which can be augmented by TKI treatment through inhibition of RNA polymerase II phosphorylation. No mutations were found in spliceosomal genes. Therefore, monitoring IS functional BCR-ABL extracting BCR-ABL^Ins35bp would lead us to a correct evaluation of MR status, thus determining the adequate therapeutic intervention.
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PMID:Tyrosine kinase inhibitors induce alternative spliced BCR-ABL^Ins35bp variant via inhibition of RNA polymerase II on genomic BCR-ABL. 3231 54


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