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 numbers, structures and functions of centrosomes in chronic myeloid leukaemia (CML) may influence cell proliferation and genomic instability, which are features of the disease. Centrosomes are regulators of mitotic spindle orientation and can act as scaffolds for centrosome-associated regulators of the cell cycle. This study showed, for the first time, that p210(BCR-ABL1) and p145(ABL1) are both centrosome-associated proteins, as demonstrated by co-immunoprecipitation with the pericentriolar protein, pericentrin. Furthermore, when CML cells were treated with imatinib there was a 55% and 20% reduction of p210(BCR-ABL1) and p145(ABL1) binding to pericentrin, respectively. Cell lines expressing p210(BCR-ABL1) and primary CD34(+) cells from CML patients exhibited more numerical and structural centrosomal abnormalities than p210(BCR-ABL1) negative cells. Primary cells from CML blast crisis (BC) patients exhibited a distinctive amorphous staining pattern of pericentrin compared to normal and CML chronic phase (CP) patients, suggesting a possible defect in pericentrin localisation at the centrosomes. Proteins, such as aurora kinases, pericentrin, survivin and separase, regulate centrosome structure and function, cell cycle and mitotic spindle formation. Levels of the protease, separase are abnormally high in CML CP and BC cells in comparison to normal CD34(+) cells. The data imply that expression of p210(BCR-ABL1) is associated with abnormalities in the centrosome-centriole cycle and increased separase expression.
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PMID:Abnormal centrosome-centriole cycle in chronic myeloid leukaemia? 1956 13

B cell lineage acute lymphoblastic leukemia (ALL) arises in virtually all cases from B cell precursors that are arrested at pre-B cell receptor-dependent stages. The Philadelphia chromosome-positive (Ph(+)) subtype of ALL accounts for 25-30% of cases of adult ALL, has the most unfavorable clinical outcome among all ALL subtypes and is defined by the oncogenic BCR-ABL1 kinase and deletions of the IKAROS gene in >80% of cases. Here, we demonstrate that the pre-B cell receptor functions as a tumor suppressor upstream of IKAROS through induction of cell cycle arrest in Ph(+) ALL cells. Pre-B cell receptor-mediated cell cycle arrest in Ph(+) ALL cells critically depends on IKAROS function, and is reversed by coexpression of the dominant-negative IKAROS splice variant IK6. IKAROS also promotes tumor suppression through cooperation with downstream molecules of the pre-B cell receptor signaling pathway, even if expression of the pre-B cell receptor itself is compromised. In this case, IKAROS redirects oncogenic BCR-ABL1 tyrosine kinase signaling from SRC kinase-activation to SLP65, which functions as a critical tumor suppressor downstream of the pre-B cell receptor. These findings provide a rationale for the surprisingly high frequency of IKAROS deletions in Ph(+) ALL and identify IKAROS-mediated cell cycle exit as the endpoint of an emerging pathway of pre-B cell receptor-mediated tumor suppression.
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PMID:Pre-B cell receptor-mediated cell cycle arrest in Philadelphia chromosome-positive acute lymphoblastic leukemia requires IKAROS function. 1962 Jun 27

The 2008 WHO classification system for hematological malignancies is comprehensive and includes histology and genetic information. Myeloid neoplasms are now classified into five categories: acute myeloid leukemia, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN, and myeloid and/or lymphoid malignancies associated with eosinophilia and PDGFR or FGFR1 rearrangements. MPN are subclassified into eight separate entities: chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis, systemic mastocytosis, chronic eosinophilic leukemia not otherwise specified, chronic neutrophilic leukemia, and unclassifiable MPN. The diagnosis of chronic myelogenous leukemia requires the presence of BCR-ABL1, while its absence is required for all other MPN. Additional MPN-associated molecular markers include mutations of JAK2, MPL, TET2 and KIT. JAK2 V617F is found in most patients with polycythemia vera, essential thrombocythemia, or primary myelofibrosis and is, therefore, useful as a clonal marker in those settings. The diagnostic utility of MPL and TET2 mutations is limited by low mutational frequency. In systemic mastocytosis, presence of KIT D816V is expected but not essential for diagnosis. Chronic eosinophilic leukemia not otherwise specified should be distinguished from both PDGFR-rearranged or FGFR1-rearranged neoplasms and hypereosinophilic syndrome. We discuss histologic, cytogenetic and molecular changes in MPN and illustrate their integration into practical diagnostic algorithms.
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PMID:Myeloproliferative neoplasms: contemporary diagnosis using histology and genetics. 1980 46

Activating JAK2 V617F mutation is present in many patients with chronic myeloproliferative neoplasms. We evaluated, retrospectively, clinical and laboratory data from 70 patients with BCR-ABL1 negative, JAK2 positive, chronic myeloproliferative disease. Quantity of the JAK2 mutant allele was tested for correlation with the clinical presentation, type of chronic myeloproliferative disease, hemoglobin level, white blood cell and platelet counts, spleen size, and/or cardiovascular complications. RealTime-PCR was used for amplification of DNA from marrow or peripheral blood. Polycythemia vera was more frequently diagnosed among patients with >or=50% mutational load than among those with <50% mutational load (71% vs 25%; p = 0.003). Patients with >or=50% mutational load had higher mean white blood cell count (18.6 billion/L vs 11.3 billion/L; p = 0.043). Essential thrombocythemia patients were more likely to have <50% mutational load (48% vs 7%; p = 0.005). Splenomegaly was more frequent in patients with >or=50% mutational load independent of the diagnosis (89% vs 48%; p = 0.03). Cardiovascular complications were reported in 50% of patients with >or=50% mutational load vs 21% of patients with <50% mutational load. JAK2 quantitation was highest in polycythemia vera followed by chronic myeloproliferative disease, unclassifiable, and essential thrombocythemia patients. JAK2 quantitation appears important in clinical evaluation. Mutational load appears to be helpful in stratification of patients into subgroups with different frequency of complications. Quantitation of JAK2 mutational load may be useful in evaluating response to therapy.
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PMID:Correlation of JAK2 V617F mutant allele quantitation with clinical presentation and type of chronic myeloproliferative neoplasm. 1988 Jul 61

The somatic mutation JAK2 V617F is associated with BCR-ABL1-negative myeloproliferative neoplasms. Detection of this mutation aids diagnosis of these neoplasms, and quantification of JAK2 V617F may provide a method to monitor response to therapy. For these reasons, we designed a clinical assay that uses allele-specific PCR and real-time detection with hydrolysis probes for the quantification of JAK2 V617F, wild-type JAK2, and GAPDH transcripts. Mutant and wild-type JAK2 were quantified by using external plasmid standards that contain the relevant JAK2 V617F or JAK2 sequence, respectively. We tested 55 peripheral blood specimens from patients with suspected myeloproliferative neoplasms and 55 peripheral blood specimens from patients not known to have myeloproliferative neoplasms. Low-level, nonspecific amplification was detected in reactions containing a high copy number of plasmid standards and in specimens from patients not known to have myeloproliferative neoplasms, necessitating the use of a laboratory-established mutant to wild-type cutoff. The limit of detection established by using cell line dilutions is 0.1%, and this method identified three JAK2 V617F-positive patients who were not detected by a less sensitive method. The assay characteristics and our initial evaluation indicate this method can be used for the detection and quantification of JAK2 V617F, which should be useful for diagnosis of myeloproliferative neoplasms and potentially for monitoring minimal residual disease in future trials of therapies targeted to myeloproliferative neoplasms.
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PMID:Design and evaluation of a real-time PCR assay for quantification of JAK2 V617F and wild-type JAK2 transcript levels in the clinical laboratory. 1995 96

Targeted therapy in the form of selective tyrosine kinase inhibitors (TKI) has transformed the approach to management of chronic myeloid leukemia (CML) and dramatically improved patient outcome to the extent that imatinib is currently accepted as the first-line agent for nearly all patients presenting with CML, regardless of the phase of the disease. Impressive clinical responses are obtained in the majority of patients in chronic phase; however, not all patients experience an optimal response to imatinib, and furthermore, the clinical response in a number of patients will not be sustained. The process by which the leukemic cells prove resistant to TKIs and the restoration of BCR-ABL1 signal transduction from previous inhibition has initiated the pursuit for the causal mechanisms of resistance and strategies by which to surmount resistance to therapeutic intervention. ABL kinase domain mutations have been extensively implicated in the pathogenesis of TKI resistance, however, it is increasingly evident that the presence of mutations does not explain all cases of resistance and does not account for the failure of TKIs to eliminate minimal residual disease in patients who respond optimally. The focus of exploring TKI resistance has expanded to include the mechanism by which the drug is delivered to its target and the impact of drug influx and efflux proteins on TKI bioavailability. The limitations of imatinib have inspired the development of second generation TKIs in order to overcome the effect of resistance to this primary therapy. (Clin Cancer Res 2009;15(24):7519-27).
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PMID:Mechanisms of Resistance to Imatinib and Second-Generation Tyrosine Inhibitors in Chronic Myeloid Leukemia. 2000 52

T-cell acute lymphoblastic leukemia (T-ALL) is the result of multiple oncogenic insults of thymocytes. Recently, new ABL1 fusion genes have been identified that provide proliferation and survival advantage to lymphoblasts. These are the NUP214-ABL1 fusion gene, on amplified episomes, the unique case of EML1-ABL1 fusion due to a cryptic t(9;14)(q34;q32) and the seldom reported BCR-ABL1 and ETV6-ABL1 chimeric genes. The most frequent and strictly associated with T-ALL is the NUP214-ABL1 fusion identified in 6% of cases, in both children and adults. Patients present with classical T-ALL features. Cytogenetically, the fusion is cryptic but seen by FISH on amplified episomes or more rarely as a small hsr. The ABL1 fusion is a late event associated with other genetic alterations like NOTCH1 activating mutation, deletion of CDKN2A locus, and ectopic expression of TLX1 or TLX3. The mechanism of activation of the NUP214-ABL1 protein is unique and requires localization at the nucleopore complex and interaction with other nuclear pore proteins for crossphosphorylation and constitutive kinase activity. The ABL1 fusion proteins are sensitive to tyrosine kinase inhibitors, which can be included in future treatment strategy.
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PMID:ABL1 rearrangements in T-cell acute lymphoblastic leukemia. 2007 70

Early B cell development depends on a network of transcription factors, whereby E2A and EBF1 regulate B cell specification and Pax5 controls B-lineage commitment. In contrast, activation of the transcription factor STAT5 in response to IL-7R signaling promotes cell survival by activating the prosurvival gene Mcl1 and orders immunoglobulin gene rearrangement by repressing Igk recombination in pro-B cells. Subsequently, it cooperates with the pre-B cell receptor to facilitate pre-B cell expansion. STAT5 also plays a key role in the generation of B cell precursor acute lymphoblastic leukemia, whereby the BCR-ABL1 translocation or the collaboration of JAK2 mutations with overexpression of the thymic stromal lymphopoietin receptor CRLF2 results in constitutive STAT5 activation leading to cytokine-independent survival and growth of leukemic cells.
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PMID:STAT5 in B cell development and leukemia. 2022 68

Myeloproliferative neoplasms (MPNs) originate from genetically transformed hematopoietic stem cells that retain the capacity for multilineage differentiation and effective myelopoiesis. Beginning in early 2005, a number of novel mutations involving Janus kinase 2 (JAK2), Myeloproliferative Leukemia Virus (MPL), TET oncogene family member 2 (TET2), Additional Sex Combs-Like 1 (ASXL1), Casitas B-lineage lymphoma proto-oncogene (CBL), Isocitrate dehydrogenase (IDH) and IKAROS family zinc finger 1 (IKZF1) have been described in BCR-ABL1-negative MPNs. However, none of these mutations were MPN specific, displayed mutual exclusivity or could be traced back to a common ancestral clone. JAK2 and MPL mutations appear to exert a phenotype-modifying effect and are distinctly associated with polycythemia vera, essential thrombocythemia and primary myelofibrosis; the corresponding mutational frequencies are approximately 99, 55 and 65% for JAK2 and 0, 3 and 10% for MPL mutations. The incidence of TET2, ASXL1, CBL, IDH or IKZF1 mutations in these disorders ranges from 0 to 17%; these latter mutations are more common in chronic (TET2, ASXL1, CBL) or juvenile (CBL) myelomonocytic leukemias, mastocytosis (TET2), myelodysplastic syndromes (TET2, ASXL1) and secondary acute myeloid leukemia, including blast-phase MPN (IDH, ASXL1, IKZF1). The functional consequences of MPN-associated mutations include unregulated JAK-STAT (Janus kinase/signal transducer and activator of transcription) signaling, epigenetic modulation of transcription and abnormal accumulation of oncoproteins. However, it is not clear as to whether and how these abnormalities contribute to disease initiation, clonal evolution or blastic transformation.
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PMID:Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. 2042 94

Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm that involves primarily the megakaryocytic lineage. After many years, a few patients with ET may develop bone marrow (BM) fibrosis and rarely develop osteosclerosis. A 60-yr-old female was admitted due to severe left upper quadrant abdominal discomfort. She had been diagnosed as ET 19 yrs ago. On liver computed tomography severe splenomegaly was shown. Laboratory tests revealed WBC 24.3x10(9)/L, hemoglobin 13.4 g/dL, platelets 432x10(9)/L, lactate dehydrogenase 4,065 IU/L (reference range; 240-480). Blood smear demonstrated leukoerythroblastosis, teardrop cells, and giant and hypogranular platelets. BM study revealed inadequate aspirate due to dry tap. BM biopsy showed clusters of dysplastic megakaryocytes, grade 3 fibrosis, and severe osteosclerosis. Major/minor BCR-ABL1 rearrangement and JAK2 V617F mutation were not detected. Cytogenetic studies revealed normal karyotype. According to the 2008 WHO diagnostic criteria, the patient was diagnosed as having post-essential thrombocythemia myelofibrosis with severe osteosclerosis.
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PMID:[A case of post-essential thrombocythemia myelofibrosis with severe osteosclerosis]. 2044 28


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