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)

Blast crisis is the most advanced stage of chronic myelogenous leukemia (CML) and is highly refractory to therapy. CML is caused by expression of the chimeric BCR-ABL tyrosine kinase oncogene, the product of the t(9;22) Philadelphia translocation. Imatinib (Glivec, formerly STI571) is a rationally developed, orally administered inhibitor of the Bcr-Abl tyrosine kinase. A total of 260 patients with CML were enrolled in a phase II trial, of whom 229 had a confirmed diagnosis of CML in blast crisis. Patients were treated with imatinib in daily oral doses of 400 mg or 600 mg. Imatinib induced hematologic responses in 52% of patients and sustained hematologic responses lasting at least 4 weeks in 31% of patients, including complete hematologic responses in 8%. For patients with a sustained response, the estimated median response duration was 10 months. Imatinib induced major cytogenetic responses in 16% of patients, with 7% of the responses being complete. Median survival time was 6.9 months. Nonhematologic adverse reactions were frequent but generally mild or moderate. Episodes of severe cytopenia were also frequent and were attributable to the underlying condition and treatment with imatinib. Drug-related adverse events led to discontinuation of therapy in 5% of patients, most often because of cytopenia, skin disorders, or gastrointestinal reactions. These results demonstrate that imatinib has substantial activity and a favorable safety profile when used as a single agent in patients with CML in blast crisis. Additional clinical studies are warranted to explore the efficacy and feasibility of imatinib used in combination with other antileukemic drugs.
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PMID:Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. 1198 4

The t(9;22) chromosomal translocation results in expression of P210(BCR-ABL), a fusion protein necessary for the development of chronic myelogenous leukemia (CML). The constitutive activation of the P210(BCR-ABL) tyrosine kinase results in phosphorylation of multiple signaling pathways leading to the transformed phenotype. Additionally, extracellular interactions between P210(BCR-ABL)-expressing progenitor cells and bone marrow stroma may provide external signals that facilitate CML development. In contrast to the intracellular signaling pathways involved in CML, little is known about how P210(BCR-ABL) expression modifies cell-cell and cell-substratum interactions. To investigate the role of P210(BCR-ABL) in modulating cellular adhesion, we used a highly sensitive and quantitative cell detachment apparatus that measures the strength of association between a population of cells and an adhesive matrix. Our findings show that P210(BCR-ABL) expression increased adhesion nearly 2-fold between the myeloblastic cell line, 32D, and fibronectin compared to a control vector. We then investigated whether abnormal adhesion due to P210(BCR-ABL) expression was caused by its tyrosine kinase activity. A quantitative analysis of cell-fibronectin adhesion found that neither expression of a kinase-inactive P210(BCR-ABL) mutant in 32D cells or attenuation of kinase activity by STI571 (imatinib mesylate) in 32D cells transduced with wild-type P210(BCR-ABL) could correct the nearly 2-fold increase in cell-fibronectin adhesion. Similarly, STI571 treatment of Meg-01 cells, a P210(BCR-ABL)-expressing cell line derived from a patient in blast crisis, failed to inhibit adhesion to fibronectin. Together, our results indicate that changes in adhesion induced by P210(BCR-ABL) are independent of its tyrosine kinase activity.
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PMID:BCR-ABL-induced adhesion defects are tyrosine kinase-independent. 1201 Aug 16

We report a 53-year-old man with lymphoid blast crisis of Ph+ chronic myeloid leukaemia who was treated with STI571, a selective inhibitor of the enzymatic activity of BCR-ABL. He responded excellently to STI571 (600 mg/d), obtaining a complete cytogenetic remission after 3 months of therapy. Although remission in the bone marrow was sustained, the patient developed an isolated central nervous system relapse. Subsequent analyses of STI571 concentrations in the cerebrospinal fluid (CSF) revealed 2-log lower CSF levels of STI571 than corresponding plasma levels. These are the first data demonstrating a low penetration of orally administered STI571 into the CSF in humans.
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PMID:Low concentrations of STI571 in the cerebrospinal fluid: a case report. 1202 32

Constitutive activation of tyrosine kinases, such as the BCR/ABL fusion associated with t(9;22)(q34;q22), is a hallmark of chronic myeloid leukemia (CML) syndromes in humans. Expression of BCR/ABL is both necessary and sufficient to cause a chronic myeloproliferative syndrome in murine bone marrow transplantation models, and absolutely depends on kinase activity. Progression of CML to acute leukemia (blast crisis) in humans has been associated with acquisition of secondary chromosomal translocations, including the t(7;11)(p15;p15) resulting in the NUP98/HOXA9 fusion protein. We demonstrate that BCR/ABL cooperates with NUP98/HOXA9 to cause blast crisis in a murine model. The phenotype depends both on expression of BCR/ABL and NUP98/HOXA9, but tumors retain sensitivity to the ABL inhibitor STI571 in vitro and in vivo. This paradigm is applicable to other constitutively activated tyrosine kinases such as TEL/PDGFbetaR. These experiments document cooperative effects between constitutively activated tyrosine kinases, which confer proliferative and survival properties to hematopoietic cells, with mutations that impair differentiation, such as the NUP98/HOXA9, giving rise to the acute myeloid leukemia (AML) phenotype. Furthermore, these data indicate that despite acquisition of additional mutations, CML blast crisis cells retain their dependence on BCR/ABL for proliferation and survival.
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PMID:A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9. 1203 33

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder characterized by genomic instability leading to its inevitable clinical evolution from an easily controlled chronic phase to a terminal blastic phase. The molecular abnormality responsible for this disease--BCR-ABL--and the critical biochemical aberrations resulting from it have been studied in depth. These discoveries have led to the development of a molecule, STI571, that specifically inhibits the abnormal kinase enzymatic activity exhibited by BCR-ABL. Early results of clinical trials using STI571 have shown responses even in blast crisis. There has also been striking hematologic and cytogenetic remission rates in patients with advanced chronic phase disease, with very little toxicity. It is our opinion that this molecule will revolutionize the treatment of CML. Furthermore, the path leading to its discovery will become a paradigm for cancer therapeutics. At the time of this writing, STI571 remains investigational (although it is widely believed that it will be approved for clinical use in the United States this year ). Although suggested therapy for a disease does not generally incorporate medications that are still investigational, in this case, the impact of a still investigational agent cannot be ignored. The current data suggest that STI571 will be the treatment of choice for patients with advanced or resistant chronic phase. To date, STI571 has not been studied adequately in untreated CML patients. Even so, it is our feeling that, based on its compelling success in patients with interferon-refractory and advanced disease and on its benign side effect profile, it will quickly become the front-line therapy for CML once it becomes available. Despite the ease of administration of STI571, patients should continue to be encouraged to participate in clinical studies so that several vital issues can be resolved: 1) the percentage of untreated CML patients who will eventually develop molecular remissions; 2) the proportion of patients in whom resistance to STI571 will emerge; 3) the optimum length of treatment; and 4) the impact on survival. Because interferon-alfa can also result in cytogenetic remissions, albeit in a small percent (less than 20%) of early chronic phase patients, it seems reasonable to suggest that patients who do not attain cytogenetic/molecular remissions with STI571 alone be treated with a combination of STI571 and interferon-alfa. Patients who are resistant to STI571 with or without interferon-alfa should undergo allogeneic hematopoietic cell transplant. Salvage therapy after transplant may include donor lymphocyte infusions, interferon-alfa, additional transplant, and perhaps STI571. Medications such as hydroxyurea appear destined to play a very limited role in CML. They may be used in the palliative treatment of older STI571-resistant patients or those without a transplant donor, although these patients may be best served by being considered for clinical trials of molecules, such as polyethylene glycol-interferon-alfa, on other novel agents.
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PMID:Chronic myelogenous leukemia in chronic phase. 1205 24

We describe two Philadelphia chromosome-positive chronic myeloid leukaemia (Ph-positive CML) patients carrying micro-bcr (micro-bcr) breakpoint, who developed blast crisis within 5 years of diagnosis. Reverse transcription polymerase chain reaction analysis of bone marrow cells using primers specific for the p210BCR-ABL fusion transcript showed aberrant large-sized bands in both cases (986 bp in patient 1 and 1031 bp in patient 2). Sequencing analysis of these products revealed BCR-ABL fusion transcripts with e19a2 in patient 1 and e191a in patient 2. These findings suggest that CML carrying micro-bcr breakpoint may exhibit a similar clinical course to classical CML, and that it may not be a mild form of the disease.
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PMID:Blast crisis of Philadelphia chromosome-positive chronic myeloid leukaemia carrying micro-bcr breakpoint (e19a2 and e191a). 1210 Jan 56

Chronic myelogenous leukemia (CML), characterized by the BCR-ABL gene rearrangement, has been extensively studied. Significant progress has been made in the area of BCR-ABL-mediated intracellular signaling, which has led to a better understanding of BCR-ABL-mediated clinical features in chronic phase CML. Disease progression and blast crisis CML is associated with characteristic non-random cytogenetic and molecular events. These can be viewed as increased oncogenic activity or loss of tumor suppressor activity. However, what causes transformation and disease progression to blast crisis is only poorly understood. This is in part due to the lack of a good in vivo model of chronic phase CML even though animal models developed over the last few years have started to provide insights into blast crisis development. Thus, additional in vitro and in vivo studies will be needed to provide a complete understanding of the contribution of BCR-ABL and other genes to disease progression and to improve therapeutic approaches for blast crisis CML.
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PMID:Chronic myelogenous leukemia: mechanisms underlying disease progression. 1214 76

Using human acute leukemia HL-60/Bcr-Abl (with ectopic expression of p185 Bcr-Abl) and K562 cells (with endogenous expression of p210 Bcr-Abl) subjected to a continuous selection pressure of up to 1.0 micro M Gleevec (imatinib mesylate, STI-571), we have isolated Gleevec-resistant K562 R (+Bcr-Abl), K562 R (-Bcr-Abl), and HL-60/Bcr-Abl R cells, which display disparate level and activity of Bcr-Abl tyrosine kinase (TK). As compared with their sensitive counterparts, Gleevec-resistant cell types were >/=5-fold resistant to Gleevec-induced apoptosis. Bcr-Abl protein levels were significantly increased in HL-60/Bcr-Abl R and K562 R (+Bcr-Abl) cells, but K562 R (-Bcr-Abl) cells showed a marked decline in the mRNA and protein levels and activity of Bcr-Abl. Bcr-Abl TK level and activity corresponded to the signal transducers and activators of transcription-5 DNA binding activity and up-regulation of heat shock protein 70 levels. The decline in Bcr-Abl expression and TK activity in K562 R (-Bcr-Abl) cells was associated with reduced AKT kinase and signal transducers and activators of transcription-5 DNA binding activities and increased sensitivity to the death ligand Apo-2 ligand/tumor necrosis factor-related apoptosis-inducing ligand and 1-beta-D-arabinofuranosylcytosine-induced apoptosis. All Gleevec-resistant cell types were sensitive to 17-allylamino-17-demethoxygeldanamycin (17-AAG)- and PD180970 (a SRC and Bcr-Abl TK inhibitor)-induced apoptosis. Treatment with 17-AAG or PD180970 also induced apoptosis of CD34+ leukemic cells from three patients with chronic myeloid leukemia in blast crisis who had progressive leukemia while receiving Gleevec therapy. Taken together, these findings indicate that in addition to overexpression or mutations in Bcr-Abl, resistance to Gleevec may also develop due to a loss of Bcr-Abl expression. These findings also support the rationale to test the in vivo efficacy of 17-AAG and PD180970 against STI-571-resistant Bcr-Abl-positive acute leukemias.
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PMID:Molecular characterization and sensitivity of STI-571 (imatinib mesylate, Gleevec)-resistant, Bcr-Abl-positive, human acute leukemia cells to SRC kinase inhibitor PD180970 and 17-allylamino-17-demethoxygeldanamycin. 1238 36

Selective inhibition of the BCR-ABL tyrosine kinase by imatinib (STI571, Glivec/Gleevec) is a promising new therapeutic strategy in patients with chronic myelogenous leukemia (CML). Despite significant hematologic and cytogenetic responses, resistance occurs, particularly in patients with advanced disease. We sought to determine the underlying mechanisms. Sixty-six patients with CML in myeloid blast crisis (n = 33), lymphoid blast crisis (n = 2), accelerated phase (n = 16), chronic phase (n = 13), and BCR-ABL-positive acute lymphoblastic leukemia (n = 2) resistant to imatinib were investigated. Median duration of imatinib therapy was 148 days (range 6-882). Patients were evaluated for genomic amplification of BCR-ABL, overexpression of BCR-ABL transcripts, clonal karyotypic evolution, and mutations of the imatinib binding site in the BCR-ABL tyrosine kinase domain. Results were as follows: (1) Median levels of BCR-ABL transcripts, were not significantly changed at the time of resistance but 7/55 patients showed a >10-fold increase in BCR-ABL levels; (2) genomic amplification of BCR-ABL was found in 2/32 patients evaluated by fluorescence in situ hybridization; (3) additional chromosomal aberrations were observed in 19/36 patients; (4) point mutations of the ABL tyrosine kinase domain resulting in reactivation of the BCR-ABL tyrosine kinase were detected in 23/66 patients. In conclusion, although the heterogeneous development of imatinib resistance is challenging, the fact that BCR-ABL is active in many resistant patients suggests that the chimeric oncoprotein remains a good therapeutic target. However, patients with clonal evolution are more likely to have BCR-ABL-independent mechanisms of resistance. The observations warrant trials combining imatinib with other agents.
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PMID:Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. 1239 61

Chronic myeloid leukaemia (CML) is caused by the product of the BCR-ABL oncogene, located on the Philadelphia (Ph) chromosome. BCR-ABL is generated as a result of a reciprocal t(9;22) chromosomal translocation. The mechanisms responsible for this illegitimate recombination event remain elusive but are presumed to require a close spatial association of the translocation partners (chromosomes 9 and 22). BCR-ABL fusion transcripts can be detected by a sensitive reverse transcription-polymerase chain reaction (RT-PCR) in the leucocytes of some healthy individuals suggesting that chromosomal translocations may occur frequently in the general population. The presence of BCR-ABL fusion transcripts does not imply that the individual will inevitably develop CML since other conditions must be favourable for expansion of the abnormal clone. Breakpoints in the ABL gene occur within a 5' segment. BCR-ABL fusion transcripts lack ABL exon a1 and consist of BCR exons fused directly to ABL exon a2. The breakpoints in the BCR gene on chromosome 22 are found within three defined regions. Depending on the position of the BCR breakpoint, fusion genes are generated that encode 190-, 210- or 230-kD forms of the Bcr-Abl tyrosine kinase. Since the ABL component of the fusion gene is largely invariant, it follows that variability in disease phenotype may be due to protein sequences encoded by the translocation partner, BCR. Different disease phenotypes are associated with each of the three Bcr-Abl oncoproteins, p190(Bcr-Abl), p210(Bcr-Abl )and p230(Bcr-Abl). Mechanisms associated with malignant transformation include altered cellular adhesion, activation of mitogenic signalling pathways, inhibition of apoptosis and proteasomal degradation of physiologically important cellular proteins. CML is subject to an inexorable progression from an 'indolent' chronic phase to a terminal blast crisis. Disease progression is presumed to be associated with the phenomenon of genomic instability.
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PMID:Cytogenetic and molecular genetic aspects of chronic myeloid leukaemia. 1243 15


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