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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic myelogenous leukemia (CML) is a malignant disease resulting from the neoplastic transformation of a hematopoietic stem cell. Generation of the BCR-ABL fusion gene plays an essential role in causing the vast majority of CML. Clinical and laboratory studies have indicated that development of CML involves both the effects of BCR-ABL within its correct target cells and interactions of BCR-ABL target cells with the rest of the in vivo environment, and that the progression of the disease to blast crisis involves multiple genetic alterations. An efficient mouse bone marrow transduction and transplantation model for CML has recently been developed. This review summarizes the analysis of the roles of functional domains and downstream signaling pathways of BCR-ABL, of altered cytokine production, of interferon signaling pathways and of oncogene cooperation in the pathogenesis of CML using this murine model. The in vivo studies of leukemogenesis will help to advance mechanism-based therapies for CML, as well as to understand fundamental rules of leukemogenesis and hematopoiesis.
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PMID:The molecular mechanism of chronic myelogenous leukemia and its therapeutic implications: studies in a murine model. 1247 9

Cytoreductive therapy can ameliorate symptoms in chronic myeloid leukemia (CML) but only treatment beyond hematologic remission aiming to affect the leukemic clone can improve prognosis. Up to now bone marrow transplantation is the only established therapy with the potential to completely eliminate the BCR-ABL positive cell population. Interferon-alpha (IFN-alpha) as well as cytosine arabinoside (ARA-C), particularly in combination, have been shown to be effective in achieving cytogenetic remission in some patients. With Glivec (STI-571) there is now a drug available which can induce major cytogenetic response in more than half of the patients who have failed IFN-alpha treatment and thus possibly delay or prevent blast crisis. Recent reports, however, have shown that primitive, quiescent, Philadelphia-positive stem cells are insensitive to STI-571 in vitro. Such cells could be the basis of relapse after termination of Glivec-therapy.
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PMID:[Treatment of residual disease in chronic myeloid leukemia with STI-571 (Glivec)]. 1250 64

Natural killer (NK) cells decrease in function during chronic myelogenous leukemia (CML) progression from chronic phase to blast crisis, and they can become BCR/ABL(+) late in the disease course. To study this altered function, NK92 cells were transduced with the BCR/ABL oncogene. In contrast to the parental cells, which died when deprived of interleukin 2 (IL-2), p210(+) NK92 cells proliferated and survived indefinitely in the absence of IL-2. BCR/ABL also decreased the natural cytotoxicity of NK92 cells against K562 targets, without affecting IL-2, interferon gamma (IFN-gamma), or tumor necrosis factor alpha (TNF-alpha) production. Although the ABL-specific tyrosine kinase inhibitor imatinib mesylate (STI-571) had no effect on parental NK92 cells, it markedly decreased the growth and survival of IL-2-independent p210(+) NK92 cells. In contrast to the parental cell line, serial analysis of p210(+) NK92 cells detected small populations that clonally expressed one or more killer immunoglobulin-like receptors (KIRs). Unlike the decreased natural cytotoxicity, the function of the activating CD158j receptor remained intact. Southern blotting and hybridization with an enhanced green fluorescence protein (eGFP) probe showed that KIR(-) and KIR(+) NK92 cells were all derived from the same clone, suggesting that KIR acquisition remains dynamic at the maturational stage represented by the NK92 cell line. When tested in primary CD56(+bright) NK cells, p210 induced partial IL-2-independent growth and increased KIR expression similar to findings in NK92 cells. This is the first study to show that BCR/ABL, well known for its effects on the myeloid lineage, can alter the function of lymphoid cells, which may be associated with the defect in innate immunity associated with CML progression.
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PMID:BCR/ABL alters the function of NK cells and the acquisition of killer immunoglobulin-like receptors (KIRs). 1251 22

The onset of accelerated phase or blast crisis of chronic myelocytic leukemia (CML) is usually associated with the acquisition of new chromosome abnormalities in addition to the t(9;22)(q34;q11) that is characteristic of the chronic phase CML. We describe the cytogenetic and molecular genetic findings in two cases of myelocytic blast crisis of CML, one occurring 6 months after commencing treatment with the ABL-specific tyrosine kinase inhibitor imatinib mesylate (STI571, Glivec, or Gleevec) and the second treated with imatinib mesylate for established blast crisis. In both cases, multiple secondary cytogenetic abnormalities were observed at transformation, with homogeneously staining regions that were shown to contain BCR/ABL amplification by fluorescence in situ hybridization appearing after imatinib mesylate administration. BCR/ABL amplification is emerging as an important mechanism of acquired resistance to imatinib mesylate.
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PMID:BCR/ABL amplification in chronic myelocytic leukemia blast crisis following imatinib mesylate administration. 1254 54

BCR-ABL fusion oncogene is the molecular hallmark of chronic myelogenous leukemia (CML), a condition characterized by a progression from a chronic to acute phase leukemia because of secondary genetic events, the nature of which remains largely unknown. Here, we report that the expression of the p210 BCR-ABL fusion protein leads to a down-regulation of BRCA1 protein, a gene product involved in the maintenance of genome integrity. BRCA1 protein is nearly undetectable in leukemia cells from patients with CML, both during the chronic phase and in blast crisis. Similarly, stable transfection-enforced expression of p210 protein in established hematopoietic cell lines leads to severe BRCA1 depletion. The lack of significant change in BRCA1 mRNA level in cells expressing p210 supports the hypothesis that the regulation of BRCA1 protein level occurs after transcription. It is abolished on exposure of the cells to STI571 and by mutation in the adenosine triphosphate (ATP) pocket of p210 and thus seems to require the tyrosine kinase activity of BCR-ABL. Cell lines expressing high levels of BCR-ABL display an increased rate of sister chromatid exchange and chromosome aberrations after ionizing radiation. These findings reveal a novel link between the oncoprotein BCR-ABL and the tumor-suppressor protein BRCA1.
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PMID:Down-regulation of BRCA1 in BCR-ABL-expressing hematopoietic cells. 1257 38

Imatinib mesylate, a specific inhibitor of the BCR-ABL tyrosine kinase, has been very effective in the treatment of chronic myeloid leukemia (CML) in chronic phase with high rates of hematological and cytogenetic remissions. Resistance to therapy can develop and transformation to blast crisis may occur, particularly in patients without a cytogenetic response. We report a case of a patient with CML treated in chronic phase who developed blast crisis; withdrawal of imatinib mesylate resulted in spontaneous reversion to chronic phase.
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PMID:Spontaneous reversion from blast to chronic phase after withdrawal of imatinib mesylate in a patient with chronic myelogenous leukemia. 1261 34

Real-time reverse-transcription polymerase chain reaction (RT-PCR) (qPCR) of the BCR-ABL mRNA is a suitable technique to measure the amount of circulating leukemic cells in chronic myelogenous leukemia (CML). In this study, we evaluated a BCR-ABL-specific qPCR method using the LightCycler technology in 95 patients with Philadelphia chromosome positive acute leukemia (n = 7) or CML in different stages (n = 88). Primers and hybridization probes were chosen to detect the most prevalent variants of BCR-ABL (b2a2, b3a2, b2a3, b3a3, e19a2, e1a2) with a sensitivity of 10-5 for b2a2 and b3a2. With median BCR-ABL/G6PDH ratios of 10.7% in the untreated chronic phase, 43.2% in the newly diagnosed accelerated phase, and 131.4% in newly diagnosed blast crisis the BCR-ABL mRNA levels varied significantly between different stages of CML whereas no difference was found between blast crisis and untreated acute leukemias (136.9%). There was a strong relationship between qPCR results and cytogenetics in patients treated with imatinib, interferon-alpha, or following allografting. Thirteen patients with CML were sequentially examined by qPCR following myeloablative or non-myeloablative allogeneic peripheral blood stem cell transplantation. Five patients received donor lymphocytes and became BCR-ABL negative as confirmed by nested RT-PCR. The gradual disappearance of BCR-ABL positive cells could be monitored by qPCR following non-myeloablative transplantation. Comparison of BCR-ABL levels with the degree of donor chimerism showed that 91% of samples with complete donor chimerism were BCR-ABL negative. In 22% of BCR-ABL negative samples chimerism between 71% and 98% was observed, indicating the persistence of normal recipient's hematopoietic cells. In conclusion, the qPCR protocol used in this study is a reliable and fast method for monitoring molecular response in CML.
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PMID:Quantitative real-time reverse-transcription polymerase chain reaction for diagnosis of BCR-ABL positive leukemias and molecular monitoring following allogeneic stem cell transplantation. 1263 Dec 53

(1) Chronic myeloid leukaemia goes through three clinical phases: a chronic phase, an acceleration phase, and a terminal blast crisis. In the chronic phase, interferon alfa-2 is more effective than cytotoxic chemotherapies but it also has more adverse effects. (2) Imatinib inhibits tyrosine kinase, an enzyme encoded by the pathological gene BCR-ABL, which is created during a reverse translocation between chromosomes 9 and 22 (characteristic of chronic myeloid leukaemia). This translocation almost always creates the pathological chromosome Philadelphia in blood cell lines. (3) 1 027 patients were recruited to three non comparative trials of imatinib, each focusing on a different phase of chronic myeloid leukaemia. Efficacy was evaluated largely on the basis of blood cell count and clearance of cells harbouring the Philadelphia chromosome. (4) During the chronic phase, in patients in whom interferon alfa-2 had failed or been poorly tolerated, a major cytogenetic response, lasting at least one month, occurred in 35% of patients on imatinib, compared to 20% of patients on interferon alfa-2 + cytarabine (historical comparison). It is not known whether this translated into longer survival. (5) Preliminary results from a randomised but unblinded trial comparing imatinib with interferon + cytarabine seem to favour imatinib. Some patients developed relapses resistant to imatinib, owing to mutations in the BCR-ABL gene. (6) In patients going through the acceleration phase or blast crisis, imatinib did not improve survival compared with standard treatments. (7) The main adverse effects so far described with imatinib are gastrointestinal problems, oedema and fluid retention, and muscle and joint pain, which prompted patients to stop treatment in no more than 5% of cases. (8) Imatinib has a strong potential to interact with other drugs, including paracetamol, but few specific studies have been done. (9) In practice imatinib may be a useful option during the chronic phase, after interferon alfa-2 has failed or been stopped because of adverse effects, provided that its benefits, so far shown only in surrogate endpoints, translate into longer survival. During the acceleration phase and blast crisis imatinib may cause fewer side effects than existing treatments.
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PMID:Imatinib: new preparation. For Chronic myeloid leukaemia: further assessment required. 1266 27

We report the response to the ABL kinase inhibitor imatinib mesylate (STI571) in a patient with chronic myeloid leukemia (CML) who relapsed twice after dose-reduced allogeneic stem cell transplantation (alloSCT) for B lymphoid blast crisis (BC) and failed to develop an antileukemic response despite grade 3 graft-versus-host disease (GvHD). Complete hematologic, cytogenetic and molecular responses were achieved within 9 weeks of therapy and are maintained after 27 months. Extensive chronic skin GvHD necessitating immunosuppressive therapy developed after 14 months. This case illustrates the ability of imatinib to induce sustained hematologic and molecular remissions in some patients relapsing with advanced stage CML after alloSCT.
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PMID:Stable molecular remission induced by imatinib mesylate (STI571) in a patient with CML lymphoid blast crisis relapsing after allogeneic stem cell transplantation. 1269 30

Chronic myeloid leukemia (CML) is characterized by formation of a BCR-ABL fusion gene, usually as a consequence of the Philadelphia (Ph) translocation between chromosomes 9 and 22. Recently the development of new fluorescence in-situ hybridization (FISH) techniques has allowed identification of unexpected deletions of the reciprocal translocation product, the derivative chromosome 9, in 10% to 15% of patients with CML. These deletions are large, span the translocation breakpoint, and occur at the same time as the Ph translocation. Such deletions therefore give rise to previously unsuspected molecular heterogeneity from the very beginning of this disease, and there is mounting evidence for similar deletions associated with other translocations. Several studies have demonstrated that CML patients who carry derivative chromosome 9 deletions exhibit a more rapid progression to blast crisis and a shorter survival. Deletion status is independent of, and more powerful than, the Sokal and Hasford/European prognostic scoring systems. The poor prognosis associated with deletions is seen in patients treated with hydroxyurea or interferon, and preliminary evidence suggests that patients with deletions may also have a worse outcome than nondeleted patients following stem cell transplantation or treatment with imatinib. Poor outcome cannot be attributed to loss of the reciprocal ABL-BCR fusion gene expression alone, and is likely to reflect loss of one or more critical genes within the deleted region. The molecular heterogeneity associated with the Philadelphia translocation provides a new paradigm with potential relevance to all malignancies associated with reciprocal chromosomal translocations and/or fusion gene formation.
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PMID:Double jeopardy from a single translocation: deletions of the derivative chromosome 9 in chronic myeloid leukemia. 1273 Jan 17


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