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)

We describe a case of Philadelphia chromosome-positive chronic myeloid leukemia (Ph-positive CML) expressing p190(BCR-ABL). Reverse transcription-polymerase chain reaction (RT-PCR) analysis of bone marrow cells showed a 472-bp band using primers specific for the p190(BCR-ABL) but not p210(BCR-ABL) transcript. Sequencing analysis revealed that the PCR product was derived from the fusion between BCR exon e1 and ABL exon a2 (e1a2). CML expressing p190(BCR-ABL) is relatively rare. In a review of the literature, it may be grouped into 2 categories; approximately half of the patients exhibited prominent monocytosis and intermediate hematological phenotype between CML and chronic myelomonocytic leukemia, and the remaining patients showed no monocytosis.
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PMID:Philadelphia chromosome-positive chronic myeloid leukemia expressing p190(BCR-ABL). 1252 Nov 92

The role of allogeneic transplantation for myeloproliferative diseases other than chronic myeloid leukemia is not well established. In all, 20 patients with a median age of 51 years underwent allogeneic hematopoietic stem cell transplantation (HSCT) for myelofibrosis (n=5), chronic myelomonocytic leukemia (CMML) (n=8) and Philadelphia (Ph) chromosome-negative/BCR-ABL-negative chronic myeloid leukemia (CML) (n=7) in our institution. Patients who developed acute leukemia prior to HSCT were excluded from this analysis. A total of 15 patients received related and five patients received unrelated donor transplants. One patient failed to engraft. After a median follow-up of 17.5 months, actuarial survival at 2 years was 47% (95% CI 2%-67%), and disease-free survival 37% (95% CI 17-58%). Allogeneic transplantation may provide a therapeutic option for patients with myelofibrosis, CMML and Ph chromosome-negative/BCR-ABL-negative CML.
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PMID:Allogeneic transplantation: a therapeutic option for myelofibrosis, chronic myelomonocytic leukemia and Philadelphia-negative/BCR-ABL-negative chronic myelogenous leukemia. 1504 41

A somatic mutation in the JH2 autoinhibitory domain of the Janus kinase 2 (JAK2) tyrosine kinase was recently described in polycythemia vera, essential thrombocythemia, and myelofibrosis with myeloid metaplasia. The prevalence of this mutation in either "atypical" myeloproliferative disorders (MPDs) or the myelodysplastic syndromes (MDSs) is unknown. Bone marrow-derived genomic DNA from 245 patients--119 with chronic myelomonocytic leukemia (CMML), 101 with MDS, 11 with hypereosinophilic syndrome (HES), 8 with systemic mastocytosis (SM), and 6 with chronic neutrophilic leukemia (CNL)--was screened for the JAK2 V617F mutation. A mutant allele was detected in 11 patients: 3 with CMML (3%), 5 with MDS (5%), 2 with SM, and 1 with CNL. Interestingly, one of the patients with SM and the patient with CNL with JAK2 V617F had a history of lymphoma, and this patient with SM also had associated myelofibrosis and CMML. The current observation strengthens the specific association between JAK2 V617F and classic MPD, but also suggests an infrequent occurrence in other myeloid disorders.
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PMID:The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both "atypical" myeloproliferative disorders and myelodysplastic syndromes. 1586 Jun 61

An activating 1849G>T mutation of JAK2 (Janus kinase 2) tyrosine kinase was recently described in chronic myeloproliferative disorders (MPDs). Its role in other hematologic neoplasms is unclear. We developed a quantitative pyrosequencing assay and analyzed 374 samples of hematologic neoplasms. The mutation was frequent in polycythemia vera (PV) (86%) and myelofibrosis (95%) but less prevalent in acute myeloid leukemia (AML) with an antecedent PV or myelofibrosis (5 [36%] of 14 patients). JAK2 mutation was also detected in 3 (19%) of 16 patients with Philadelphia-chromosome (Ph)-negative chronic myelogenous leukemia (CML), 2 (18%) of 11 patients with megakaryocytic AML, 7 (13%) of 52 patients with chronic myelomonocytic leukemia, and 1 (1%) of 68 patients with myelodysplastic syndromes. No mutation was found in Ph(+)CML (99 patients), AML M0-M6 (28 patients), or acute lymphoblastic leukemia (20 patients). We conclude that the JAK2 1849G>T mutation is common in Ph(-) MPD but not critical for transformation to the acute phase of these diseases and that it is generally rare in aggressive leukemias.
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PMID:JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome-negative CML, and megakaryocytic leukemia. 1603 87

Activating mutations in tyrosine kinases have been identified in hematopoietic and nonhematopoietic malignancies. Recently, we and others identified a single recurrent somatic activating mutation (JAK2V617F) in the Janus kinase 2 (JAK2) tyrosine kinase in the myeloproliferative disorders (MPDs) polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. We used direct sequence analysis to determine if the JAK2V617F mutation was present in acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML)/atypical chronic myelogenous leukemia (aCML), myelodysplastic syndrome (MDS), B-lineage acute lymphoblastic leukemia (ALL), T-cell ALL, and chronic lymphocytic leukemia (CLL). Analysis of 222 patients with AML identified JAK2V617F mutations in 4 patients with AML, 3 of whom had a preceding MPD. JAK2V617F mutations were identified in 9 (7.8%) of 116 CMML/a CML samples, and in 2 (4.2%) of 48 MDS samples. We did not identify the JAK2V617F disease allele in B-lineage ALL (n = 83), T-cell ALL (n = 93), or CLL (n = 45). These data indicate that the JAK2V617F allele is present in acute and chronic myeloid malignancies but not in lymphoid malignancies.
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PMID:The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. 1608 87

A recurrent somatic activating mutation in the nonreceptor tyrosine kinase JAK2 (JAK2V617F) occurs in the majority of patients with the myeloproliferative disorders polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, and, less commonly, chronic myelomonocytic leukemia. We do not understand the basis for the specificity of the JAK2V617F mutation in clonal disorders of the myeloid, but not lymphoid, lineage, nor has the basis for the pleiotropic phenotype of JAK2V617F-associated myeloproliferative disorders been delineated. However, the presence of the identical mutation in patients with related, but clinicopathologically distinct, myeloid disorders suggests that interactions between the JAK2V617F kinase and other signaling molecules may influence the phenotype of hematopoietic progenitors expressing JAK2V617F. Here, we show that coexpression of the JAK2V617F mutant kinase with a homodimeric Type I cytokine receptor, the erythropoietin receptor (EpoR), the thrombopoietin receptor, or the granulocyte colony-stimulating-factor receptor, is necessary for transformation of hematopoietic cells to growth-factor independence and for hormone-independent activation of JAK-STAT signaling. Furthermore, EpoR mutations that impair erythropoietin-mediated JAK2 or STAT5 activation also impair transformation mediated by the JAK2V617F kinase, indicating that JAK2V617F requires a cytokine receptor scaffold for its transforming and signaling activities. Our results reveal the molecular basis for the prevalence of JAK2V617F in diseases of myeloid lineage cells that express these Type I cytokine receptors but not in lymphoid lineage cells that do not.
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PMID:Expression of a homodimeric type I cytokine receptor is required for JAK2V617F-mediated transformation. 1636 88

To study the prevalence of the Val617Phe JAK2 mutation in familial cases of myeloproliferative disorder (MPD) and its possible implication as a predisposing genetic factor, we analyzed 72 families including 174 patients (81 polycythemia vera [PV], 68 essential thrombocythemia [ET], 11 myelofibrosis with myeloid metaplasia [MMM], 12 chronic myeloid leukemia), 1 systemic mastocytosis, and 1 chronic myelomonocytic leukemia (CMML). The JAK2 mutation was found in three quarters of patients with PV and MMM and in half of patients with ET. Among 46 families with at least 2 cases of PV, ET, or MMM, the JAK2 mutation was absent in 6 families, heterogeneously distributed in 18, and present in all MPD patients in 22. Among these 22 families, the absence of the JAK2 mutation both in purified T and B cells in 13 unrelated patients and the observation of variable ratios of the JAK2 mutant allele in patient leucocytes indicated that the Val617Phe JAK2 mutation was acquired in familial MPDs. The JAK2 mutation was present in natural killer cells in two thirds of tested patients (27 of 40), suggesting its occurrence in a multipotent hematopoietic progenitor cell. The analysis of the hematologic profile showed that the homozygous JAK2 mutation confers a proliferative advantage and is associated with the progression of the hematologic disease.
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PMID:Genetic and clinical implications of the Val617Phe JAK2 mutation in 72 families with myeloproliferative disorders. 1653 3

The majority of chronic myelomonocytic leukemia (CMML) cases arise de novo; cases evolving from preexisting myelodysplasia (MDS) or myeloproliferative diseases have not been well-studied. We conducted the present study to determine the clinicopathologic features and to study possible underlying molecular and cytogenetic mechanisms involved in this evolution. Between April 1995 and November 2005, we identified 120 CMML cases, of which 20 (16.7%) had a previous diagnosis of MDS. Of the 20 patients with MDS, 6 had relative monocytosis at diagnosis. At the time of MDS to CMML evolution, mutations in JAK2 (V617F), FLT3 (ITD), K-ras-2, or N-ras were not acquired, and only 1 (6%) of 17 evaluable cases showed cytogenetic progression. The median time to evolution from MDS to CMML was 29 months, and the median survival following CMML development was 13 months. Three cases (17%) transformed to acute myeloid leukemia. These findings indicate that in some cases of otherwise typical MDS, the progenitor cells may have some capacity for monocytic proliferation at diagnosis and manifest rapid disease progression once a monocytic proliferation supervenes.
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PMID:Chronic myelomonocytic leukemia evolving from preexisting myelodysplasia shares many features with de novo disease. 1705 76

Myeloproliferative disorders, including chronic idiopathic myelofibrosis (CIMF), polycythemia vera (PV), essential thrombocythemia (ET), and chronic myelomonocytic leukemia (CMML), are clonal diseases of hematopoietic stem or precursor cells. They often show a protracted or chronic course; however, all have the potential of progressing to severe marrow failure, associated with myelofibrosis, or of transforming into acute leukemia. At that point, hematopoietic cell transplantation (HCT) is the only current treatment strategy with curative potential. If transplantation is being considered and a suitable donor is available, HCT should be carried out before leukemic transformation has occurred, as the success rate of HCT declines steeply in patients who have evolved to leukemia. As many as 75-80% of patients with the original diagnoses of PV or ET, about 65-70% with CIMF, and 45% of patients with CMML are surviving long term after allogeneic HCT using conventional transplant regimens, with follow-up now extending to 15 years. Results with HLA-identical related and unrelated donors are comparable. Major risk factors for the outcome after HCT are the disease stage, the presence of comorbid conditions, and patient age. The development of reduced-intensity conditioning regimens has allowed for successful HCT even for older patients and patients with comorbid conditions. Studies on disease mechanisms, including the recent characterization of an activating mutation in JAK2, may provide additional prognostic guidance and are likely to lead to the development of novel treatment strategies, which will require continuous reassessment as to the optimum timing of HCT.
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PMID:Hematopoietic cell transplantation for chronic myeloproliferative disorders. 1712 83

Myeloproliferative disorders (MPDs) constitute a group of hematopoietic malignancies that feature enhanced proliferation and survival of one or more myeloid lineage cells. William Dameshek is credited for introducing the term "MPDs" in 1951 when he used it to group chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) under one clinicopathologic category. Since then, other myeloid neoplasms have been added to the MPD member list: chronic neutrophilic (CNL), eosinophilic (CEL) and myelomonocytic (CMML) leukemias; juvenile myelomonocytic leukemia (JMML); hypereosinophilic syndrome (HES); systemic mastocytosis (SM); and others. Collectively, MPDs are stem cell-derived clonal proliferative diseases whose shared and diverse phenotypic characteristics can be attributed to dysregulated signal transduction--a consequence of acquired somatic mutations. The most recognized among the latter is BCR-ABL, the disease-causing mutation in CML. Other mutations of putative pathogenetic relevance in MPDs include: JAK2V617F in PV, ET, and PMF; JAK2 exon 12 mutations in PV; MPLW515L/K in PMF and ET; KITD816V in SM; FIP1L1-PDGFRA in CEL-SM; rearrangements of PDGFRB in CEL-CMML and FGFR1 in stem cell leukemia-lymphoma syndrome; and RAS/PTPN11/NF1 mutations in JMML. This increasing repertoire of mutant molecules has streamlined translational research and molecularly targeted drug development in MPDs.
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PMID:Oncogenes in myeloproliferative disorders. 1735 42


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