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)

Leukocytes contribute to the pathogenesis of thrombosis in essential thrombocythemia (ET) through recently discovered mechanisms of activation and interaction with platelets and endothelial cells. To evaluate whether an increased leukocyte count was associated with thrombosis and whether this effect can be modulated by therapy, we analyzed the clinical course of 439 patients with ET followed at the Ospedali Riuniti di Bergamo. The strength of the association was measured at diagnosis or before thrombotic events by multivariable analyses carried out using data at baseline as well as time-varying covariates. The results showed that (1) an increased leukocyte count at diagnosis was associated with thrombosis during follow-up ("baseline analysis," relative risk [RR] 2.3, 95% confidence interval [CI] 1.4-3.9, P = .001); (2) hydroxyurea (HU) lowered leukocytosis and reduced the strength of the association between leukocytosis and thrombosis ("time-dependent analysis," RR 1.6, 95% CI 0.9-2.0, not significant [NS]); (3) the association of leukocytosis and thrombosis was more evident in untreated low-risk patients (RR 2.7, 95% CI 1.2-6.4, P = .01) compared with HU-treated high-risk patients (RR 1.6, 95% CI 0.8-3.2, NS); and (4) the presence of JAK2 V617F was not identified as a risk factor for thrombosis during follow-up despite a significant association between the mutation and leukocytosis. We suggest validation of these findings in prospective clinical studies.
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PMID:Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status. 1711 Apr 52

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

The identification of JAK2V617F mutations in polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis (MF) represents an important advance in our understanding of these myeloproliferative disorders (MPD). Most, if not all, patients with PV and a significant number of patients with ET and MF are JAK2V617F positive, and the mutation likely arises in the hematopoietic stem cell compartment. JAK2V617F is a constitutively active tyrosine kinase that is able to activate JAK-STAT signaling most efficiently when co-expressed with the erythropoietin receptor (EPOR), the thrombopoietin receptor (MPL), or the granulocyte colony-stimulating factor receptor (GCSFR). Data from murine models supports the central role of JAK2V617F in the pathogenesis of MPD, as expression of JAK2V617F in a bone marrow transplantation assay results in polycythemia and myelofibrosis in recipient mice. Activation of JAK-STAT signaling by JAK2V617F in some, but not all MPD patients with ET and MF led to the identification of the constitutively active MPLW515L allele in ET and MF. Small molecule inhibitors of JAK-STAT signaling are currently being developed, which offer potential for molecularly targeted therapy for patients with PV, ET, and MF. Despite these advances, many questions remain regarding the role of a single disease allele in three phenotypically distinct MPD, the potential clinical efficacy of JAK2 inhibitors, and the identity of oncogenic alleles in JAK2V617F/MPLW515-negative MPD.
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PMID:Role of JAK-STAT signaling in the pathogenesis of myeloproliferative disorders. 1712 66

JAK2V617F, a somatic gain-of-function mutation involving the JAK2 tyrosine kinase gene, occurs in nearly all patients with polycythemia vera (PV) but also in a variable proportion of patients with other myeloid disorders; mutational frequency is estimated at approximately 50% in both essential thrombocythemia (ET) and myelofibrosis (MF), up to 20% in certain subcategories of atypical myeloproliferative disorder (atypical MPD), less than 3% in de novo myelodysplastic syndrome (MDS) or acute myeloid leukemia, and 0% in chronic myeloid leukemia (CML). Accordingly, there is now molecular justification for grouping PV, ET, and MF together in a distinct MPD category (i.e., classic, BCR-ABL(-) MPD) that is separate from chronic myeloid leukemia (CML), MDS, and atypical MPD. To date, JAK2V617F has not been described in patients with reactive myeloproliferation, lymphoid disorders, or solid tumor. Therefore, the presence of JAK2V617F strongly suggests an underlying MPD and it is therefore reasonable to consider JAK2V617F-based laboratory tests for the evaluation of polycythemia, primary thrombocytosis, unexplained leukocytosis, bone marrow fibrosis, or abdominal vein thrombosis. Current information on disease-specific prognostic relevance of JAK2V617F is inconclusive and confounded by inter-study differences in the performance of mutation screening assays. Regardless, the discovery of JAK2V617F has reinforced the pathogenetic contribution of JAK-STAT signaling in MPD and identifies JAK2 as a valid drug target.
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PMID:Classification, diagnosis and management of myeloproliferative disorders in the JAK2V617F era. 1712 67

The JAK2(V617F) mutation is present in almost all patients with polycythemia vera (PV), large proportions of patients with essential thrombocythemia and idiopathic myelofibrosis, and less frequently in atypical myeloproliferative disorders (MPD). We show that transplantation of JAK2(V617F)-transduced bone marrow into BALB/c mice induces MPD reminiscent of human PV, characterized by erythrocytosis, granulocytosis, extramedullary hematopoiesis, and bone marrow fibrosis, but not thrombocytosis. Fluorescence-activated cell sorting of bone marrow and spleen showed proportional expansion of common myeloid progenitors, granulocyte-monocyte and megakaryocyte-erythrocyte progenitors. Megakaryocyte and late erythroid progenitors were dramatically increased, with only modest expansion of early erythroid progenitors. Erythropoietin (Epo) receptor expression was reduced on early, but normal on late erythroblasts. Serum levels of Epo and granulocyte colony-stimulating factor, but not granulocyte macrophage colony-stimulating factor, were reduced, whereas tumor necrosis factor-alpha was increased, possibly exerting a negative effect on JAK2(V617F)-negative hematopoiesis. These data suggest that erythrocytosis and granulocytosis in JAK2(V617F) mice are the net result of a complex interplay between cell intrinsic and extrinsic factors. There were no thromboembolic events and no animals succumbed to their disease, implicating additional factors in the manifestation of human disease. The disease was not transplantable and prolonged observation showed normalization of blood counts in most JAK2(V617F) mice, suggesting that the mutation may not confer self-renewal capacity.
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PMID:Characterization of murine JAK2V617F-positive myeloproliferative disease. 1714 59

JAK2(V617F), a mutant of tyrosine kinase JAK2, is found in most patients with polycythemia vera (PV) and a substantial proportion of patients with idiopathic myelofibrosis or essential thrombocythemia. The JAK2 mutant displays a much increased kinase activity and generates a PV-like phenotype in mouse bone marrow transplant models. This study shows that the anti-cancer drug erlotinib (Tarceva) is a potent inhibitor of JAK2(V617F) activity. In vitro colony culture assays revealed that erlotinib at micro-molar concentrations effectively suppresses the growth and expansion of PV hematopoietic progenitor cells while having little effect on normal cells. Furthermore, JAK2(V617F)-positive cells from PV patients show greater susceptibility to the inhibitor than their negative counterparts. Similar inhibitory effects were found with the JAK2(V617F)-positive human erythroleukemia HEL cell line. These data suggest that erlotinib may be used for treatment of JAK2(V617F)-positive PV and other myeloproliferative disorders.
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PMID:Erlotinib effectively inhibits JAK2V617F activity and polycythemia vera cell growth. 1717 22

Essential thrombocythemia (ET) is an acquired myeloproliferative disorder (MPD) characterized by a sustained elevation of platelet number with a tendency for thrombosis and hemorrhage. The prevalence in the general population is approximately 30/100,000. The median age at diagnosis is 65 to 70 years, but the disease may occur at any age. The female to male ratio is about 2:1. The clinical picture is dominated by a predisposition to vascular occlusive events (involving the cerebrovascular, coronary and peripheral circulation) and hemorrhages. Some patients with ET are asymptomatic, others may experience vasomotor (headaches, visual disturbances, lightheadedness, atypical chest pain, distal paresthesias, erythromelalgia), thrombotic, or hemorrhagic disturbances. Arterial and venous thromboses, as well as platelet-mediated transient occlusions of the microcirculation and bleeding, represent the main risks for ET patients. Thromboses of large arteries represent a major cause of mortality associated with ET or can induce severe neurological, cardiac or peripheral artery manifestations. Acute leukemia or myelodysplasia represent only rare and frequently later-onset events. The molecular pathogenesis of ET, which leads to the overproduction of mature blood cells, is similar to that found in other clonal MPDs such as chronic myeloid leukemia, polycythemia vera and myelofibrosis with myeloid metaplasia of the spleen. Polycythemia vera, myelofibrosis with myeloid metaplasia of the spleen and ET are generally associated under the common denomination of Philadelphia (Ph)-negative MPDs. Despite the recent identification of the JAK2 V617F mutation in a subset of patients with Ph-negative MPDs, the detailed pathogenetic mechanism is still a matter of discussion. Therapeutic interventions in ET are limited to decisions concerning the introduction of anti-aggregation therapy and/or starting platelet cytoreduction. The therapeutic value of hydroxycarbamide and aspirin in high risk patients has been supported by controlled studies. Avoiding thromboreduction or opting for anagrelide to postpone the long-term side effects of hydrocarbamide in young or low risk patients represent alternative options. Life expectancy is almost normal and similar to that of a healthy population matched by age and sex.
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PMID:Essential thrombocythemia. 1721 76

Chromosomal aberrations in polycythemia vera (PV) are heterogenous and nonrandom. A prognostic predictive value of these aberrations has not been established. The V617F mutation in the JAK2 gene on chromosome 9p24.1 was identified recently in peripheral blood leukocytes in the majority of patients with PV and in approximately half of patients with essential thrombocythemia and idiopathic myelofibrosis. Within the JAK2 V617F-positive PV patients, however, clinical presentation and degree of myeloproliferation varies to a great extent. Here we report four cases of chronic myeloproliferative disorders [two with PV, one with PV in transformation to idiopathic myelofibrosis (IMF) and one IMF patient], with the distinct karyotypic abberations der(18) t(9;18) (p13;p11) and der(9;18)(p10;q10). Two patients had hyperproliferative PV and two had "transitional PV" and IMF, respectively. All four patients harbored the JAK2 V617F mutation. Our data, together with previously published data, clearly indicate an association of these chromosomal abnormalities with a highly proliferative PV phenotype with a propensity to transform into postpolycythemic myelofibrosis. Cytogenetic analysis seems to identify a subgroup of patients with a distinct prognostic profile, and should be performed in conjunction with a JAK2 mutation analysis in patients suspected of a chronic myeloproliferative disease.
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PMID:A der(18)t(9;18)(p13;p11) and a der(9;18)(p10;q10) in polycythemia vera associated with a hyperproliferative phenotype in transformation to postpolycythemic myelofibrosis. 1721 18

The Philadelphia chromosome (Ph)-negative myeloproliferative disorders (MPDs) include essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), and polycythemia vera (PV). All of these disorders are clonal hematologic malignancies originating at the level of the pluripotent hematopoietic stem cell. Recently, activating mutations of the intracellular cytokine-signaling molecule JAK2 have been identified in > 90% of patients with PV and in 50% of those with IMF and ET. In addition, a mutation of the thrombopoietin receptor, MPLW515L, has been documented in some patients with IMF. Both mutations activate JAK-STAT signaling pathways and likely play a role in disease progression. Both ET and PV are associated with prolonged clinical courses associated with frequent thrombotic and hemorrhagic events, and progression to myelofibrosis and acute leukemia. IMF has a much poorer prognosis and is associated with cytopenias, splenomegaly, extramedullary hematopoiesis, and bone marrow fibrosis. Stratification of risk for the development of complications from Ph-negative MPDs has guided the identification of appropriate therapies for this population. Intermediate/high-risk IMF or myelofibrosis after ET or PV is associated with a sufficiently poor prognosis to justify the use of allogeneic stem cell transplantation, which is capable of curing such patients. Reduced-intensity conditioning in preparation for allogeneic stem cell transplantation has permitted older patients with IMF to undergo transplantation with increasing success.
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PMID:Philadelphia chromosome-negative myeloproliferative disorders: biology and treatment. 1722 72

We compared the laboratory and clinical findings of 179 patients with essential thrombocythemia (ET) and 77 with polycythemia vera (PV) classified according to the presence of the JAK2 V617F mutation. A gradient was observed in laboratory values between patients with JAK2 wild-type ET, JAK2 V617F ET and PV (all of whom carried the JAK2 mutation). The rate of thrombotic complications in JAK2-positive ET patients was significantly higher than that in wild-type ET patients and not statistically different from that in PV patients.
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PMID:Risk of thrombosis in patients with essential thrombocythemia and polycythemia vera according to JAK2 V617F mutation status. 1722 51


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