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)

Abnormal circulation and unregulated proliferation of chronic myelogenous leukemia (CML) progenitors is related, at least in part, to BCR/ABL induced abnormalities in beta1 integrin-mediated adhesion and signaling. The BCR/ABL oncogene has several potential interactions with cytoskeletal elements that are important for normal integrin signaling. In the present study, we evaluated whether abnormalities in beta1 integrin-cytoskeletal interactions were present in primary CML progenitors and contributed to defective integrin function. beta1 integrin-cytoskeletal interactions were studied in CML and normal CD34+ primary hematopoietic progenitors as well as BCR/ABL-transfected or mock-transfected M07e cells. In normal CD34+ progenitors, antibody-mediated cross-linking of beta1 integrins resulted in their redistribution into caps via a process requiring receptor-cytoskeletal interactions. CML CD34+ cells demonstrated significantly impaired beta1 integrin capping. This defect was related to the presence of the BCR/ABL gene, because capping also was impaired in BCR/ABL-transfected M07e cells. Defective receptor capping was not seen for non-integrin receptors. In addition, CML CD34- and M07eBCR/ABL cells also demonstrated increased actin polymerization and altered actin cytoskeletal organization. Further studies suggested that impaired beta1 integrin capping and defective integrin-mediated adhesion and proliferation inhibition in CML cells were related to abnormally enhanced integrin-cytoskeletal association and restricted receptor mobility. Finally, interferon alpha, which restores integrin-mediated adhesion and signaling in CML progenitors, also enhanced integrin capping in CD34+ cells. These studies suggest that p210BCR/ABL induces abnormal association of integrin receptors with the cytoskeleton and restricted receptor mobility and provide new insights into mechanisms underlying abnormal integrin function in CML progenitors.
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PMID:Role of abnormal integrin-cytoskeletal interactions in impaired beta1 integrin function in chronic myelogenous leukemia hematopoietic progenitors. 1048 Apr 29

D-FISH uses DNA probes with fluorescence in situ hybridization to detect two fusion signals in cells with a t(9;22)(q34;q11.2) from patients with chronic myeloid leukemia (CML). Using D-FISH, 147 patients with CML were studied and considerable macro genetic variation was observed among their Ph-chromosomes. Typical D-FISH signal patterns were observed for 81% of patients, but three different atypical patterns were seen in 19% of patients. Atypical patterns among Ph-chromosomes were consistent with loss of the 3' portion of BCR that is usually translocated to chromosome 9, or loss of the 5' segment of ABL that usually remains on chromosome 9, or loss of both the 3' translocated BCR and 5' residual ABL hybridization sites. Atypical patterns were associated with all forms of Ph-chromosomes including t(9;22)(q34;q1.2), complex translocations and masked. The normal range for 500 interphase nuclei for patients with typical patterns is < 1%. By comparison, the normal range for patients with either of two atypical patterns was < or = 1.8% and for patients with the other atypical pattern was < or = 23%. Thus, special scoring criteria are needed to detect and quantify nuclei with atypical patterns using D-FISH. The proportion of patients that responded to therapy with interferon alpha-2b or interferon alpha-2b and ara-C for 36 patients with typical patterns was similar to 7 patients with atypical patterns.
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PMID:Atypical BCR and ABL D-FISH patterns in chronic myeloid leukemia and their possible role in therapy. 1049 71

We have identified an interferon-like cytokine, limitin, on the basis of its ability to arrest the growth of or kill lympho-hematopoietic cells. Limitin strongly inhibited B lymphopoiesis in vitro and in vivo but had little influence on either myelopoiesis or erythropoiesis. Because limitin uses the interferon alpha/beta receptors and induces interferon regulatory factor-1, it may represent a previously unknown type I interferon prototype. However, preferential B-lineage growth inhibition and activation of Janus kinase 2 in a myelomonocytic leukemia line have not been described for previously known interferons.
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PMID:Limitin: An interferon-like cytokine that preferentially influences B-lymphocyte precursors. 1083 82

The management of chronic myelogenous leukemia (CML) has become complex due to the availability of improved diagnostic procedures and life-prolonging or even curative treatment strategies that are more successful the earlier they are applied in the course of the disease. This is true for allogeneic bone-marrow transplantation, treatment with interferon alpha (IFN) and Philadelphia-negative stem-cell collections for autografting. Outcome differs according to risk profiles of patients at diagnosis. In addition, molecular techniques for the detection of the BCR-ABL fusion gene or its products, such as the reverse-transcriptase polymerase chain reaction (PCR), Southern blot analysis, or fluorescence in situ hybridization, facilitate accurate diagnosis and the monitoring of residual disease. They allow the individualization of treatment such as early infusion of donor lymphocytes if molecular relapse is detected after allografting, or discontinuation of IFN in the presence of very low BCR-ABL transcript levels). The availability of real-time PCR devices further improves and accelerates the diagnosis and monitoring of residual disease. This article addresses recent developments in drug therapy and allografting, including treatment intensification with low-dose ara C or intensive chemotherapy followed by autografting, introduction of new drugs (such as homoharringtonine or tyrosine kinase inhibitor STI571), progress with unrelated donor transplantations, use of peripheral blood stem cells for allografting, and transplantation without myeloablative conditioning. Tradeoffs between the treatment options will be discussed in the context of the evidence-based guidelines for treating CML, as recently published by the American Society of Hematology. Finally, the new competence network on acute and chronic leukemias will be introduced.
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PMID:Current trends in the management of chronic myelogenous leukemia. 1096 82

Over the last 2 decades, four major therapeutic approaches have drastically changed the prognosis in chronic myelogenous leukemia (CML): 1) allogeneic stem cell transplant (SCT); 2) interferon alpha (IFN-alpha) based regimens; 3) donor lymphocyte infusions (DLI); and 4) and the revolutionary BCR-ABL tyrosine kinase inhibitors such as STI571 (signal transduction inhibitor 571). Each modality has exploited and targeted different aspects of CML biology, and is associated with different risk-benefit ratios. In Section I of this review, Dr. Melo reviews the molecular pathophysiology of CML and potential new targets for therapy including anti-sense strategies to disrupt the BCR-ABL gene and inhibition of the BCR-ABL tyrosine kinase activity. In Section II, Dr. Tura, addresses important questions in the use of IFN-alpha for the treatment of CML, including the mechanism of action and the development of resistance, the optimal dose and duration of therapy and the prediction of response based on clinical features. An approach to the choice of therapy based on the predicted mortality is presented. In Section III Dr. Giralt presents an update on the results of unrelated donor transplantion, donor lymphocyte infusions (DLI) and non-ablative stem cell transplantation (NST) in CML. The roles of CD8-depletion, dose escalation and the transduction of suicide genes in treatment with DLI are addressed. Early results of NST in CML show that it is feasible and can result in long-term disease control. In Section IV Drs. Kantarjian and Talpaz review the results of IFN-alpha plus low-dose cytosine arabinoside and other promising modalities for CML including homoharringtonine, decitabine, and polyethylene glycol-interferon. In Section V they present an update on the recent experience with STI571. Objective but transient responses have been seen in 40% to 50% of patients in CML blastic phase. In accelerated phase, the response rate with STI571 exceeds 70%, and these responses are durable. In chronic phase CML, STI571 at 300 mg daily in patients who failed IFN-alpha produces a complete hematologic response (CHR) in over 90% of patients. Early results suggest cytogenetic response rates of approximately 50%, which may be major in approximately 30%. The maturing results with STI571 may soon change current recommendations regarding the relative roles of established modalities such as allogeneic SCT and IFN-alpha. Important questions include 1) whether STI571 therapy alone may be sufficient to induce long-term survival and event-free survival in CML, or whether it needs to be combined simultaneously or sequentially with IFN-alpha and cytosine arabinoside; and 2) what should the indications for frontline allogeneic SCT be in relation to STI571 therapy.
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PMID:Chronic Myelogenous Leukemia: Disease Biology and Current and Future Therapeutic Strategies. 1170 37

Our understanding of the pathological molecular events underlying chronic myelogenous leukemia(CML) has rapidly grown over the past 2 decades. At the same time, new therapeutic modalities for CML which can cure or prolong survival in this formerly incurable disease, including interferon alpha administration and allogeneic hematopoietic stem cell transplantation, have been established. Now, a new molecule-specific drug, a ABL tyrosine kinase inhibitor(STI571), are developing, which is offering new hope for expanded treatment options for patients with CML. Clinical investigators and medical doctors will have responsibility in helping newly diagnosed patients with CML to properly elect treatment planning among the increased options available now. This specific number of JJ CO will be hoped to provide information to many medical oncologists beyond the hematology speciality.
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PMID:[Introduction: chronic myelogenous leukemia leading advanced clinical oncology]. 1176 30

The degree of tumor load reduction as measured by cytogenetic response is an important prognostic factor for chronic myelogenous leukemia (CML) patients on therapy. We sought to determine whether BCR-ABL transcript levels can predict chromosomal response. Residual disease was evaluated in 120 CML patients in chronic phase (CP) treated with the selective tyrosine kinase inhibitor imatinib after resistance or intolerance to interferon alpha (IFN). Median time of therapy was 401 days (range 111-704). BCR-ABL and total ABL transcripts were measured in 486 peripheral blood (PB) specimens with a real time RT-PCR approach using fluorescent-labeled hybridization probes (LightCycler technology) and results were expressed as the ratio BCR-ABL/ABL. Cytogenetic response was determined in 3-monthly intervals: From 101 evaluable patients, 42 achieved a complete (CR, 0% Philadelphia chromosome (Ph)- positive metaphases), 18 a partial (PR, 1-34% Ph+), 13 a minor (MR, 35-94% Ph+), and 26 no response (NR, >94% Ph+). All PB samples were RT-PCR positive. The proportion of Ph+ metaphases and simultaneous BCR-ABL/ABL ratios correlated with r = 0.74, P < 0.0001. In order to investigate whether early molecular analysis may predict cytogenetic response, quantitative RT-PCR data obtained after 1 and 2 months of therapy were compared with cytogenetic response at 6 months. BCR-ABL/ABL ratios after 1 month were not predictive, but results after 2 months correlated with the consecutive cytogenetic response (P = 0.0008). The probability for a major cytogenetic response was significantly higher in patients with a BCR-ABL/ABL ratio <20% after 2 months of imatinib therapy. We conclude that: (1) quantitative determination of residual disease with real time RT-PCR is a reliable and sensitive method to monitor CML patients on imatinib therapy; (2) BCR-ABL/ABL ratios correlate well with cytogenetic response; (3) in IFN-pretreated patients all complete responders to imatinib have evidence of residual disease with the limited follow-up available; and (4) cytogenetic response at 6 months of therapy in CP patients is predictable with real time RT-PCR at 2 months.
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PMID:Early reduction of BCR-ABL mRNA transcript levels predicts cytogenetic response in chronic phase CML patients treated with imatinib after failure of interferon alpha. 1220 Jun 66

Rarely has progress in treatment of leukemia been as dramatic and convincing as with the BCR-ABL tyrosine kinase inhibitor imatinib.(1) Imatinib induces remissions of CML as fast as hydroxyurea, achieves rates of cytogenetic remissions that by far exceed those induced by interferon alpha and has a toxicity profile as favourable as that of hydroxyurea and much superior to that of interferon alpha.(2) In addition, the causal approach of this new drug, which may well serve as a model for new treatment modalities in other neoplasias is reassuring.
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PMID:Current CML therapy: progress and dilemma. 1276 62

Chronic myeloid leukemia (CML) in older patients has not been studied well. To assess the long-term outcome of older patients with Philadelphia- and/or BCR-ABL-positive CML, 199 patients aged >/=60 years representing 23% of 856 patients enrolled in the German randomized CML-studies I (interferon alpha (IFN) vs hydroxyurea (HU) vs busulfan (BU) and II (IFN+HU vs HU alone) were analyzed after a median observation time of 7 years. In all, 45 patients were treated with Bu, 63 with HU, and 91 with IFN. The 5-year survival was 38% in patients >/=60 years and 47% in patients <60 years (P<0.001). Whereas 5-year survival in chemotherapy-treated older patients was inferior to that in younger patients (33 vs 46%, P=0.006 for HU and 29 vs 38%, P=0.042 for Bu), no significant survival difference could be verified in IFN-treated patients (46 vs 53%, P=0.077). Calculation of age-adjusted, relative survival confirmed these results. Adverse effects of IFN were similar in both age groups, but IFN dosage to achieve treatment goals was lower in older patients. We conclude that the course of CML is not different in the elderly. They require lower IFN doses, achieve the same hematologic and cytogenetic response rates and the same survival advantage at comparable toxicity.
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PMID:Chronic myeloid leukemia in the elderly: long-term results from randomized trials with interferon alpha. 1297 Jul 82

Previously, we showed that expression of myeloma-associated (proto)oncogene fibroblast growth factor receptor 3 (FGFR-3) is increased in white blood cells from patients with chronic myeloid leukemia (CML). The abnormal expression was returned back to the normal levels as soon as these patients reconstituted their hematopoiesis following transplantation of allogeneic peripheral blood stem cells. The aims of this study were: (1) to define population(s) of cells overexpressing FGFR-3, and (2) to determine the expression of FGFR-3 during the clinical course of the disease. We show that the vast majority of FGFR-3 transcripts as well as FGFR-3 protein arise from CD34+ BCR-ABL+ cells. Although increased levels of FGFR-3 were found in majority of late chronic phase patients treated with interferon alpha or hydroxyurea, the expression of FGFR-3 was always lowered following treatment with BCR-ABL tyrosine kinase inhibitor STI571. Compared to unstimulated cells, high levels of FGFR-3 were also identified in CD34+ cells from granulocyte colony-stimulating factor-mobilized blood stem cell harvests from healthy donors, suggesting a potential growth factor-dependent basis for elevated expression of FGFR-3 in CML. These findings have implications for the involvement of FGFR-3 in malignant hematopoiesis and depict FGFR-3 tyrosine kinase in CD34+ leukemic cells as a possible target for tyrosine kinase inhibitors.
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PMID:Increased expression of fibroblast growth factor receptor 3 in CD34+ BCR-ABL+ cells from patients with chronic myeloid leukemia. 1456 21


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