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)

Selective inhibition of the BCR-ABL tyrosine kinase by imatinib (Gleevec) (formerly STI571) is a promising new therapeutic strategy in patients with chronic myelogenous leukemia (CML). Despite significant hematologic and cytogenetic responses, resistance occurs in patients with chronic phase (CP) and advanced disease. A cohort of 72 patients with CML in myeloid blast crisis (BC) (n = 34), lymphoid BC (n = 2), accelerated phase (AP) (n = 16), CP (n = 18), and BCR-ABL(+) acute lymphoblastic leukemia (ALL) (n = 2) resistant to imatinib were investigated. Median levels of BCR-ABL transcripts, determined by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR), were not significantly changed at the time of resistance, but seven of 55 patients showed a greater than 10-fold increase in BCR-ABL levels. Genomic amplification of BCR-ABL was found in two of 32 patients evaluated by fluorescence in situ hybridization (FISH). Additional chromosomal aberrations were observed in 19 of 36 patients and point mutations of the ABL tyrosine kinase domain resulting in reactivation of the BCR-ABL tyrosine kinase were detected in 29 of 72 patients. Resistance may be caused by BCR-ABL-independent or BCR-ABL-dependent mechanisms. A thorough evaluation of resistant cases is required to suggest therapeutic measures in the individual case. Clonal selection of resistant cells harboring a BCR-ABL mutation might be reversed by stopping imatinib therapy and switching to chemotherapy. Combination therapy from the start of treatment to reduce the frequency of resistance is currently being evaluated with several drugs.
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PMID:Cytogenetic and molecular mechanisms of resistance to imatinib. 1278 79

Residual disease in chronic myeloid leukemia patients may be assessed by various molecular methods. After imatinib treatment a significant proportion of patients achieve complete cytogenetic remission (CCR) and a sensitive method is necessary to monitor treatment response and to detect early signs of relapse. Reverse-transcriptase polymerase chain reaction (RT-PCR) is by far the most sensitive approach to assess residual disease in this group of patients. Qualitative PCR methods give only limited information about the residual leukemic mass. Quantitative RT-PCR (Q-PCR) assays enable to monitor the kinetics of residual BCR-ABL transcripts over time in patients with a good response to imatinib. Early Q-PCR results on imatinib treatment can help to identify individuals who are likely to have a good response. In chronic phase patients after CCR, Q-PCR may identify patients who are likely to continue with their CCR or to relapse and may help to optimize treatment for this group of patients. The definition of molecular surrogate endpoints beyond CCR for studies which are currently planned demands standardization of the nomenclature and of technologies to measure these targets.
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PMID:Molecular surveillance of chronic myeloid leukemia patients in the imatinib era - evaluation of response and resistance. 1517 8

Survival among chronic myelogenous leukemia (CML) patients can be linked to the reduction in leukemic cell burden. Treatment with imatinib mesylate results in a high frequency of complete cytogenetic response, which can be further stratified using quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). We have serially monitored peripheral blood and bone marrow BCR-ABL transcripts using qRT-PCR in CML patients commencing imatinib therapy, and compared the results with bone marrow cytogenetics. Seventeen patients (aged 25-74 yr) with Philadelphia chromosome positive CML in first chronic phase were treated with imatinib targeting a dose of 400 mg/d. The median follow up is 30 mo (range 9-33 mo). Every third month the product of the BCR-ABL fusion gene was evaluated in both blood and bone marrow specimens by real-time RT-PCR using the TaqMan probe system. In 113 simultaneously obtained blood and bone marrow samples, the BCR-ABL transcript values agreed well with cytogenetic data. Blood and bone marrow specimens gave comparable values for BCR-ABL transcripts. Before start of imatinib therapy there was a considerable variation in BCR-ABL transcripts among the patients, ranging approximately one log (base 10). Similarly, patients with a complete cytogenetic response following imatinib therapy had variable BCR-ABL transcript levels, ranging at least three logs (base 10). The major decline in BCR-ABL transcripts occurred within 6 mo after start of imatinib therapy. The decline in BCR-ABL transcripts, following imatinib therapy, appears to level off at 12-15 mo. Two late responders were identified with a still decreasing level in BCR-ABL transcripts after 24 mo of treatment. It is concluded that BCR-ABL mRNA quantification in peripheral blood is suitable for routine monitoring of the response to treatment and long-term disease status in CML, especially in patients who have achieved a complete cytogenetic response. A plateau in BCR-ABL transcripts seems to have been reached after 12-15 mo of imatinib treatment; however, some "late responders" are seen.
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PMID:Serial monitoring of BCR-ABL transcripts in chronic myelogenous leukemia (CML) treated with imatinib mesylate. 1557 19

The unique molecular characteristic of chronic myeloid leukemia (CML), the disease-causing ABL (9q34) to BCR (22q11) translocation, has provided an invaluable tool for disease diagnosis and monitoring of treatment response. The traditional standard in this regard is bone marrow karyotype, also known as conventional cytogenetics (CC), which reveals a shortened chromosome 22, the Philadelphia chromosome, t(9;22)(q34;q11). CC in CML has also been effectively used for monitoring the response to drug therapy. However, this particular laboratory test misses submicroscopic BCR/ABL translocations and is suboptimal for minimal residual disease (MRD) assessment. Both fluorescence in situ hybridization (FISH) and reverse-transcriptase polymerase chain reaction (RT-PCR) feature higher sensitivity in terms of both diagnosis and MRD assessment in CML, compared to CC. Another advantage of these alternative tests is their effective applicability to peripheral blood specimens. The current review highlights the practical literature with respect to the use of FISH for CML whereas the use of RT-PCR has been extensively covered in recent communications.
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PMID:Fluorescent in situ hybridization in the diagnosis, prognosis, and treatment monitoring of chronic myeloid leukemia. 1639 61

Imatinib mesylate (STI571), a specific Bcr-Abl inhibitor, has shown a potent antileukemic activity in clinical studies of chronic myeloid leukemia (CML) patients. Early prediction of response to imatinib cannot be anticipated. We used a standardized quantitative reverse-transcriptase polymerase chain reaction (QRT-PCR) for BCR-ABL transcripts on 191 out of 200 late-chronic phase CML patients enrolled in a phase II clinical trial with imatinib 400 mg/day. Bone marrow samples were collected before treatment, after 12, 20 and at the end of study treatment (52 weeks) while peripheral blood samples were obtained after 2, 3, 6, 10, 14, 20 and 52 weeks of therapy. The amount of BCR-ABL transcript was expressed as the ratio of BCR-ABL to beta2-microglobulin (beta2M). We show that, following initiation of imatinib, the early BCR-ABL level trends in both bone marrow and peripheral blood samples made it possible to predict the subsequent cytogenetic outcome and response. We propose this method as the method of choice for monitoring patients on imatinib therapy. QRT-PCR studies may be able to identify degrees of molecular response that predict both complete cytogenetic response and long term stability, as well as patterns of response that provide an early indication of relapse and imatinib resistance.
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PMID:Prediction of response to imatinib by prospective quantitation of BCR-ABL transcript in late chronic phase chronic myeloid leukemia patients. 1640 13

The Philadelphia chromosome (Ph) as a secondary cytogenetic abnormality is a rare event. It is observed mostly as an additional, late-appearing cytogenetic change during the evolution of acute leukemia and its presentation as a secondary change at the onset of disease is much rarer. We describe here a patient with acute myelogenous leukemia (AML) who had Ph as a secondary chromosome abnormality at diagnosis. Cytogenetic analysis showed an abnormal karyotype, 45,XY,inv(3)(q21q26),-7[4]/45,idem, t(9;22)(q34;q11.2). The p190 variety of BCR-ABL rearrangements was confirmed by a real-time reverse-transcriptase polymerase chain reaction using fluorescent probes. To our knowledge, the minor BCR-ABL fusion gene involving a secondary Ph superimposed on inv(3) and monosomy 7 has not been reported in AML at diagnosis. Along with the identification of more cases, it will be possible to understand the exact role of this secondary Ph in a multistep leukemogenesis.
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PMID:The Philadelphia chromosome as a secondary abnormality in inv(3)(q21q26) acute myeloid leukemia at diagnosis: confirmation of p190 BCR-ABL mRNA by real-time quantitative polymerase chain reaction. 1649 May 99

Nested reverse-transcriptase polymerase chain reaction (rt-PCR) was performed on 58 leukemia patients at BIRDEM Laboratory, as a pioneering work in Bangladesh. Thirty of themwere examined for the presence of BCR-ABL being clinically and morphologically diagnosed as chronic myeloid leukemia (CML) and 28 for PML-RARalpha fusion transcripts being clinically and morphologically diagnosed as acute promyelocytic leukemia (APL/ AML M3). The cases were selected for targeted therapy with imatinib mesylate and all-Trans retinoic acid (ATRA) to treat CML and APL respectively. Samples were received either before commencement or during therapy. In the positive cases, amplified DNA products were visible after gel electrophoresis and were reported accordingly. In case of BCR-ABL, positive results were found for five out of six (83.33%) untreated cases and 11 out of 24 (45.83%) treated cases. Positive results for PML-RARalpha were found for 12 out of 14 (85.70%) untreated cases and 11 out of 16 (68.75%) treated cases. A strong positive correlation was found between duration of treatment and negativity of PCR results in both the cases. In present times, the detection of minimal residual disease in patients undergoing treatment for hematological malignancies has become an important goal, not only to monitor the effectiveness of therapy but also to detect an impending relapse. This is the first time in Bangladesh that rt-PCR method is being employed to detect or monitor the presence of abnormal fusion genes in hematological malignancies.
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PMID:Rt-PCR method for diagnosis and follow-up of hematological malignancies: first approach in Bangladesh. 1878 70

A pericentric inv(9)(p22q34) of the derivative chromosome 9 that resulted from a standard t(9;22)(q34;q11.2) was identified by R-banding karyotypic analysis and fluorescence in situ hybridization (FISH) assays in 4 (0.18%) of 2,200 Philadelphia chromosome (Ph)-positive leukemia patients, including 3 with chronic myeloid leukemia (CML) in chronic phase and 1 with acute myeloid leukemia (AML) in our hospital since 2004. All four patients had two malignant clones: one with only t(9;22)(q34;q11.2) and another with der(9)t(9;22)(q34;q11.2)inv(9)(p22q34) that resulted in the separation of the ABL1/BCR fusion gene. No metaphases with only inv(9)(p22q34) were seen in any of them. FISH also found a deletion of partial sequence of BCR on der(9)t(9;22)(q34;q11.2)inv(9)(p22q34) in 67.5% of bone marrow cells in the AML patient, but did not detect the deletion of the sequence of ASS/9q34 in these four patients. Reverse transcriptase-polymerase chain reaction revealed a b3a2 type of BCR/ABL1 fusion transcript in all of them, proving their disease to be Ph-positive leukemia. On reviewing the literature, only two solitary Ph-positive leukemia patients have been noticed to have the inv(9)(p22q34) anomaly. These two patients, together with our four documented patients, indicate that inv(9)(p22q34) is a novel, rare, but recurrent secondary chromosomal abnormality for Ph-positive leukemia. Despite receiving hydroxyurea therapy (n = 3 patients), combined chemotherapy (n = 2), even imatinib treatment (n = 1), three patients, including one with AML and two with CML (one of whom progressed into the lymphoblastic blast phase), died with survival times of 28 days, 13 months, and 34 months, respectively. Only one patient with CML remained alive for 5.5 months. Their negative outcome implies that inv(9)(p22q34) has an unfavorable impact on prognosis. Presently, no firm conclusions can be drawn from this study. Because the case number reported here is very small, more patients with this anomaly need to be investigated to elucidate its true prognostic significance.
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PMID:A pericentric inv(9)(p22q34) of the der(9)t(9;22)(q34;q11.2) is a recurrent secondary anomaly in Ph-positive leukemia. 2115 55

The International Randomized Study of Interferon vs. STI571 (IRIS) trial that investigated the use of the tyrosine kinase inhibitor (TKI) imatinib (versus interferon) changed the treatment and outcome of chronic myeloid leukemia (CML). Long-term follow-up of IRIS patients has defined response parameters and methods of tracking residual disease with cytogenetic testing of bone marrow metaphases and molecular monitoring of BCR-ABL transcripts using quantitative reverse-transcriptase polymerase chain reaction. Cytogenetic and molecular responses are now considered useful surrogates for long-term outcome. Early and robust response to imatinib predicts positive long-term outcomes. However, 15-25% of patients fail initial treatment or become intolerant of imatinib and need increased doses or alternate treatment. Second-line treatment with the second-generation TKIs nilotinib and dasatinib have resulted in favorable rates of progression-free survival (PFS) and overall survival. Data from the ENESTnd (nilotinib) and DASISION (dasatinib) trials in newly diagnosed chronic-phase CML patients demonstrated more robust and rapid complete cytogenetic (77-80%) and major molecular responses (43-46%) at 12 months compared with imatinib (65-66% and 22-28%). The relationship between a complete cytogenetic response at 12 months and long-term PFS supports a role for second-generation TKIs as first-line treatment of newly diagnosed chronic-phase CML.
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PMID:Interpretation of cytogenetic and molecular results in patients treated for CML. 2141 37

The promise of the RNA interference (RNAi) technology is equally dependent on the efficiency and stability of gene silencing. The aim of the present study was the development of foamy virus (FV) vectors for stable RNAi, utilizing two potent RNA polymerase III (Pol III) promoters. Using green fluorescent protein as a target gene, we examined the efficiency of mouse U6 (mU6) and human H1 Pol III promoters in different human cell lines and mouse hematopoietic stem cells (HSCs) ex vivo and in vivo, following bone marrow transplantation. Both our mU6 and H1 FV vectors mediated very efficient gene silencing with as low as one vector copy per cell. However, transduction of human cell lines with FV vectors expressing short hairpin RNA from mU6 led to the gradual elimination of cells in culture, as opposed to H1-harboring cells, underscoring the importance of the expression system or cellular context in the evaluation of the overall RNAi effects. The efficiency and stability of the H1 vectors were further shown by the successful silencing of BCR-ABL in K562 cells. Accordingly, mU6 vectors induced efficient and stable gene silencing in mouse HSCs following bone marrow transplantation. Our work is the first in vivo study on the efficiency and stability of RNAi gene silencing in HSCs with FV vectors, currently a safe alternative for viral gene transfer.
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PMID:A foamy virus vector system for stable and efficient RNAi expression in mammalian cells. 2145 85


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