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 is a malignant disease of the hematopoietic stem cell compartment, which is characterized by expression of the BCR-ABL fusion protein. Expression of BCR-ABL allows myeloid cells to grow in the absence of the growth factors interleukin-3 and granulocyte-macrophage colony-stimulating factor. The tyrosine kinase activity of BCR-ABL constitutively activates signaling pathways associated with Ras and its downstream effectors and with the Jak/STAT pathway. Additionally, we reported previously that BCR-ABL activates the transcription factor nuclear factor-kappaB (NF-kappaB) in a manner dependent on Ras and that inhibition of NF-kappaB by expression of a modified form of IkappaBalpha blocked BCR-ABL-driven tumor growth in a xenograft model. Here, we show that a highly specific inhibitor of IkappaB kinase beta, a key upstream regulator of the NF-kappaB pathway, induces growth suppression and death in cells expressing wild-type, Imatinib-resistant, or the T315I Imatinib/Dasatinib-resistant forms of BCR-ABL. Cell cycle variables were not affected by this compound. These data indicate that blockage of BCR-ABL-induced NF-kappaB activation via IkappaB kinase beta inhibition represents a potential new approach for treatment of Imatinib- or Dasatinib-resistant forms of chronic myelogenous leukemia.
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PMID:IkappaB kinase beta inhibition induces cell death in Imatinib-resistant and T315I Dasatinib-resistant BCR-ABL+ cells. 1824 68

Chromosome translocations resulting in fusion genes have been implicated in leukemogenesis. The paradigm involves the fusion of the genes encoding BCR and ABL, leading to a constitutively active tyrosine kinase. The detection of BCR-ABL has been limited to fluorescence in situ hybridization analysis, reverse transcription-polymerase chain reaction, of mRNA, and Western blot of analysis downstream effectors in the BCR-ABL activated pathway. Here, we describe a novel immunoassay that directly measures levels of BCR-ABL fusion protein and its phosphorylation in peripheral blood plasma and cell lysates. This approach has the potential for widespread application in the detection and quantitation of other fusion genes involved in hematological malignancies.
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PMID:Detection of chromosome translocations by bead-based flow cytometry. 1860 85

Imatinib was the first BCR-ABL-targeted agent approved for the treatment of patients with chronic myeloid leukemia (CML) and confers significant benefit for most patients; however, a substantial number of patients are either initially refractory or develop resistance. Point mutations within the ABL kinase domain of the BCR-ABL fusion protein are a major underlying cause of resistance. Of the known imatinib-resistant mutations, the most frequently occurring involve the ATP-binding loop (P-loop). In vitro evidence has suggested that these mutations are more oncogenic with respect to other mutations and wild type BCR-ABL. Dasatinib and nilotinib have been approved for second-line treatment of patients with CML who demonstrate resistance (or intolerance) to imatinib. Both agents have marked activity in patients resistant to imatinib; however, they have differential activity against certain mutations, including those of the P-loop. Data from clinical trials suggest that dasatinib may be more effective vs. nilotinib for treating patients harboring P-loop mutations. Other mutations that are differentially sensitive to the second-line tyrosine kinase inhibitors (TKIs) include F317L and F359I/V, which are more sensitive to nilotinib and dasatinib, respectively. P-loop status in patients with CML and the potency of TKIs against P-loop mutations are key determinants for prognosis and response to treatment. This communication reviews the clinical importance of P-loop mutations and the efficacy of the currently available TKIs against them.
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PMID:P-loop mutations and novel therapeutic approaches for imatinib failures in chronic myeloid leukemia. 1882 13

Chronic myeloid leukemia (CML) is a progressive and often fatal malignancy of the blood. The harbinger of CML is a chromosomal translocation that results in the synthesis of the BCR-ABL fusion protein, a constitutively active tyrosine kinase. The advent of imatinib, an inhibitor targeted specifically for BCR-ABL, represented a significant medical advance in CML therapy. However, patients with CML can exhibit varying responses to first-line treatment with imatinib. While most patients respond to treatment, some may experience a loss of response or require treatment discontinuation due to toxicity. Frequent monitoring for resistance or intolerance is a requirement for recognition of suboptimal response. Mutational analysis of the patient's BCR-ABL alleles is also informative and may be predictive of a response to therapy. Published physician guidelines have highlighted these recommendations, but it is not clear if these guidelines are universally followed. One option in patients showing poor response to standard-dose imatinib of 400 mg is to escalate the dose. However, this option should be reserved for patients with minimal disease burden. Clinically available options mainly include second-generation tyrosine kinase inhibitors, such as dasatinib and nilotinib. Allogenic stem cell transplantations (for eligible patients) also should be considered. The disease and patient characteristics at the time of imatinib failure should be evaluated before choosing second-line therapy to optimize the therapeutic benefit without unnecessary delay.
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PMID:Treatment selection after imatinib resistance in chronic myeloid leukemia. 1934 97

Tyrosine kinase inhibitors have profoundly modified the treatment and prognosis of chronic myeloid leukemia and Ph(+) acute lymphoblastic leukemia. A rapid and accurate detection of the BCR-ABL fusion protein is paramount today for an optimal management of Ph(+) acute lymphoblastic leukemia. We have utilized a recently described and commercialized immunoassay that identifies qualitatively the presence of the BCR-ABL protein in leukemic cell lysates. The BCR-ABL fusion protein is captured and detected by a cytometric bead assay and analyzed by flow cytometry. The assay was applied to 101 primary patient samples (94 acute leukemias and 7 chronic myeloid leukemia blast crisis) and the results of the immunoassay were concordant with those obtained by conventional molecular techniques. The method proved reliable, reproducible, of simple execution and it was successfully completed within four hours. This flow cytometric immunoassay has important implications for perfecting the management of Ph(+) acute lymphoblastic leukemia patients worldwide.
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PMID:An accurate and rapid flow cytometric diagnosis of BCR-ABL positive acute lymphoblastic leukemia. 1999 14

Constitutive tyrosine kinase (TK) activity of p210 BCR-ABL fusion protein of chronic myeloid leukemia (CML) usurps physiological functions of normal p145 c-ABL protein. Accordingly, its inhibition by imatinib mesylate (IM) lets p145 c-ABL translocate into the nuclear compartment, which drives cell growth arrest and apoptotic death. Here we show that IM and the mammalian target of rapamycin (mTOR) inhibitor RAD001 (Everolimus) have additive effects on BCR-ABL-expressing cells. Those effects are at least partly conditional upon the enhanced nuclear accumulation of p145 c-ABL through events encompassing post-translational modifications of p145 c-ABL (Thr(735) phosphorylation) precluding its nuclear export and of 14-3-3 sigma (Ser(186) phosphorylation by c-Jun N-terminal kinase [JNK]) promoting p145 c-ABL nuclear re-import.
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PMID:mTOR inhibitor RAD001 (Everolimus) enhances the effects of imatinib in chronic myeloid leukemia by raising the nuclear expression of c-ABL protein. 1964 77

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by clonal expansion of cells in the myeloid line, expressing the BCR-ABL fusion protein responsible for the oncogenic effect of CML. The current frontline therapy in CML is the BCR-ABL tyrosine kinase inhibitor, Imatinib. Although this drug has been shown to improve survival in CML patients, its role in the context of a transplant setting has not been widely described in the literature. We report on the long term molecular remission of CML in a 55 year old man with a second renal transplant who is hepatitis C virus positive, and has associated cardiovascular and immunological risk factors.
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PMID:[Molecular remission of chronic myeloid leukaemia in a patient with hepatitis and a second kidney transplant]. 1993 7

Chronic myeloid leukemia (CML) is a hematological malignancy characterized by high levels of immature white blood cells. CML is caused by the translocation between chromosomes 9 and 22 (which results in the formation of the Philadelphia chromosome) creating BCR-ABL fusion protein. Imatinib and nilotinib are chemotherapeutic drugs which specifically bind to the BCR-ABL and inhibit cancer cells. Nilotinib is more effective in this respect than imatinib. We have shown that nilotinib induces apoptosis in imatinib-resistant K562 CML cells which have the wild-type BCR-ABL fusion gene almost to the same extent as it does in the parental sensitive cells by the increase in caspase-3 enzyme activity and the decrease in mitochondrial membrane potential. This effect of nilotinib, even in low concentrations, may indicate the efficacy of the usage of nilotinib in imatinib-resistant CML with less risk of undesired cytotoxic effects in the remaining cells of the body.
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PMID:Nilotinib significantly induces apoptosis in imatinib-resistant K562 cells with wild-type BCR-ABL, as effectively as in parental sensitive counterparts. 2013 60

Chronic myeloid leukemia (CML) is a progressive and often fatal myeloproliferative disorder. The hallmark of CML is an acquired chromosomal translocation known as the Philadelphia chromosome (Ph) that results in the synthesis of the BCR-ABL fusion protein, a constitutively active tyrosine kinase (TK). The introduction of imatinib, a TK inhibitor (TKI) specific for BCR-ABL, was a major breakthrough in CML therapy. Although most patients respond to first-line imatinib therapy, some experience a loss of response (resistance) or require treatment discontinuation because of toxicity (intolerance). In patients for whom standard-dose imatinib therapy (400 mg/day) fails, imatinib dose escalation (600-800 mg/day) is a second-line option. However, high-dose imatinib is not an appropriate approach for patients experiencing drug toxicity, and there remain questions over the durability of responses achieved with this strategy. Alternative second-line options include the newer TKIs dasatinib and nilotinib. A substantial amount of long-term data for these agents is available. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacologic profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutational status. To optimize therapeutic benefit, clinicians should select treatment based on each patient's historical response, adverse event tolerance level, and risk factors.
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PMID:Clinical algorithms for the treatment of patients with chronic myeloid leukemia: the 2010 perspective. 2052 8

Chronic Myeloid Leukemia (CML) is a hematopoietic stem cell malignancy that is driven by the oncogenic BCR-ABL fusion protein, and for which treatment with ABL tyrosine kinase inhibitors (TKI) has yielded great success. While this is the case, BCR-ABL leukemic stem cells can persist despite TKI therapy, and efforts have intensified towards determining the molecular pathways that are critical for the maintenance of such cells. Recent studies indicate that aberrant Hedgehog (Hh) signaling plays a crucial role in the survival of the leukemic stem cell population. The Hh pathway displays crucial roles during embryonic development, tissue regeneration and repair in adults. Several mechanisms that lead to the aberrant activation of the Hh pathway have been identified in various cancers. Here we review in detail the discovery that Hh signaling governs the maintenance of the critical leukemia initiating cells or leukemic stem cells (LSCs) in BCR-ABL-induced CML as well as discuss investigations on the role of Hh signaling in normal hematopoeisis. As inhibitors that directly target the positive Hh signal transducer Smoothened (SMO) have entered clinical trials, these findings offer a unique opportunity to potentially target the LSC population that is not eliminated with ABL tyrosine kinase inhibition therapy in CML.
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PMID:Hedgehog pathway activation in chronic myeloid leukemia. 2092 37


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