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)

There have been conflicting reports over the JAK2-V617F mutation status of platelets in chronic myeloproliferative diseases (CMPDs). The aim of this study was to analyse JAK2-V617F status, not only in granulocytes but also in platelets. The JAK2-V617F mutation was analysed in both granulocytes and platelets in 115 patients with CMPDs using direct sequencing. JAK2-V617F was detected in granulocytes from 71 of those patients, all 71 of whom also had platelet JAK2-V617F expression. The remaining 44 patients showed negative JAK2-V617F expression on granulocytes, but positive JAK2-V617F expression was detected on the platelets from nine of the 33 essential thrombocythaemia (ET) patients, one of the eight polycythaemia vera patients, and two of the three primary myelofibrosis patients. When ET patients were divided into three groups according to granulocyte and platelet JAK2-V617F status (both-positive, platelets-only positive and both-negative), the both-positive and platelets-only positive groups shared the clinical features of higher white blood cell count and frequent thrombosis. These results suggest that analysis of platelets is a more sensitive approach for detecting JAK2-V617F in CMPD patients than analysis of granulocytes. They also suggest that previous reports of the incidence of JAK2-V617F in CMPD patients, obtained using only analysis of granulocytes, could be underestimations.
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PMID:JAK2-V617F mutation analysis of granulocytes and platelets from patients with chronic myeloproliferative disorders: advantage of studying platelets. 1785 8

With the discovery in the last 3 years of novel Janus kinase 2 (JAK2) and thrombopoietin receptor (MPL) mutations, the pathogenetic understanding of and clinical practice for myeloproliferative neoplasms (MPNs) have entered a new era. Each one of these newly discovered mutations, including JAK2V617F, MPLW515L, and a JAK2 exon 12 mutation, has been shown to result in constitutive activation of JAK-STAT signaling and also induce a MPN phenotype in mice. Thus, JAK2 is now considered to be a legitimate target for drug development in MPNs, and small molecule JAK2 inhibitors have already gone through successful preclinical testing, and early-phase human trials in primary myelofibrosis have already begun. Furthermore, JAK2 mutation screening has now become a front-line diagnostic test in the evaluation of both "erythrocytosis" and thrombocytosis and the 2001 World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis have now been revised to incorporate JAK2V617F mutation screening.
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PMID:JAK2 mutations and clinical practice in myeloproliferative neoplasms. 1803 73

An acquired JAK2 V617F mutation is found in most patients with polycythemia vera (PV), and about half of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Mice transplanted with bone marrow cells in which JAK2 V617F was retrovirally expressed developed PV-like features, but not ET or PMF. To address the contribution of this mutation to the pathogenesis of these three MPDs, we generated two lines of JAK2 V617F transgenic mice. One line showed granulocytosis after 4 months of age. Among 43 mice, 8 (19%) showed polycythemia and 15 (35%) showed thrombocythemia. The second line showed extreme leukocytosis and thromobocytosis. They showed anemia that means Hb value from 9 to 10 g per 100 ml when 1 month old. Myeloid cells and megakaryocytes were predominant in the bone marrow of these animals, and splenomegaly was observed. The expression of JAK2 V617F mRNA in bone marrow cells was 0.45 and 1.35 that of endogenous wild-type JAK2 in the two lines, respectively. In vitro analysis of bone marrow cells from both lines showed constitutive activation of ERK1/2, STAT5 and AKT, and augmentation of their phosphorylations by cytokine stimulation. We conclude that in vivo expression of JAK2 V617F results in ET-, PMF- and PV-like disease.
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PMID:Development of ET, primary myelofibrosis and PV in mice expressing JAK2 V617F. 1803 15

Thrombocytosis is associated with inflammation, and certain inflammatory cytokines, including IFN-gamma, stimulate megakaryocyte and platelet production. However, the roles of IFN-gamma and its downstream effector STAT1 in megakaryocyte development are poorly understood. We previously reported that STAT1 expression was significantly downregulated in Gata1-knockdown murine megakaryocytes, which also have impaired terminal maturation. Here, we show that ectopic expression of STAT1, or its target effector IRF-1, rescued multiple defects in Gata1-deficient megakaryopoiesis in mice, inducing polyploidization and expression of a subset of platelet-expressing genes. Enforced expression of STAT1, IRF-1, or GATA-1 enhanced phosphorylation of STAT1, STAT3, and STAT5 in cultured Gata1-deficient murine megakaryocytes, with concomitant megakaryocyte maturation. In contrast, enhanced thrombopoietin signaling, conferred by enforced expression of constitutively active JAK2 or c-MPL, induced phosphorylation of STAT3 and STAT5, but not STAT1, and failed to rescue megakaryocyte maturation. Finally, megakaryocytes from Stat1(-/-) mice were defective in polyploidization. Together, these findings reveal a unique role for STAT1 in megakaryopoiesis and provide new insights into how GATA-1 regulates this process. Our studies elucidate potential mechanisms by which various inflammatory disorders can cause elevated platelet counts.
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PMID:STAT1 promotes megakaryopoiesis downstream of GATA-1 in mice. 1806 35

Vascular manifestations are the main clinical complication of essential thrombocythemia (ET). They include arterial thrombosis (30-40% of patients), venous thrombosis (5%), and ischemia due to microcirculatory disorders. Their incidence is highest at disease onset and diminishes gradually thereafter. The pathophysiology of ET involves dysmegakaryocytopoiesis, leading to platelet, leukocyte and vascular endothelial cell activation. The recent discovery of the V617F mutation of the JAK2 tyrosine kinase in 50-60% of patients with ET defined a new subgroup resembling polycythemia vera. This review examines biological findings and their correlation with the risk of thrombosis. Until now, stratification of the vascular risk has relied on a clinical case-control study showing that thrombotic and vascular complications are more frequent in patients over 60 and those with a history of thrombosis. These criteria, along with a rapid increase in thrombocytosis (>1500 G/L) leading to an increase in the bleeding risk, define a high-vascular-risk subgroup of patients warranting cytoreductive therapy. Although many biological markers of dysmegakaryocytopoiesis and cellular hyperactivation have been linked to an increase in the thrombotic risk, none is available for large-scale prediction of an intermediate vascular risk. The role of the JAK2 V617F mutation itself is controversial. Whatever the ET subgroup, antiplatelet therapy is largely used, based on the results of the ECLAP prospective controlled trial that showed a statistically significant reduction in thrombotic complications in patients receiving aspirin for polycythemia vera, a very similar myeloproliferative disorder.
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PMID:[Vascular complications of essential thrombocythemia]. 1807 51

An increased platelet number in blood depends on a limited spectrum of causes, which aren't always simple to identify. Secondary thrombocytosis is a reactive process in relation with acute or chronic inflammatory diseases, or asplenia. The infrequent inherited thrombocytoses disorders are suspected when similar cases are observed in the same family. However, the most frequent causes of chronic thrombocytosis in adults are the so-called chronic myeloproliferative syndromes (chronic myelocytic leukaemia, polycythemia vera, primary myelofibrosis, essential thrombocytemia), and to a lesser extent, myelodysplastic syndromes. In the course of these disorders, thrombocytosis is often the first recognized abnormality. Chronic myelocytic leukaemia is easily diagnosed owing to the presence of either the Philadelphia chromosome or the BCR-ABL fusion gene product. The next step still relies upon a distinction according to the PVSG or the WHO criteria of Polycythemia Vera (PV) and Idiopathic myelo fibrosis (IMF) to finally confirm genuine Essential Thrombocythemia (ET). The recent description of the V617F mutation of JAK2 in 90% of PV patients, 43 to 67% with IMF and 50% of ET diagnosed according to either the PVSG or the WHO criteria is a definite characteristic of clonality now accessible in haematology practice. However, this mutation is neither specific nor constant in any of the Philadelphia negative myeloproliferative disorders, which outlines the importance of the WHO criteria of megakaryocytic abnormalities on bone marrow biopsy as the hallmark of Ph negative MPDs. The exclusion of PV and of IMF, including pre fibrotic and early fibrotic forms is still required for the diagnosis of "true" ET. Disease stratification and treatment strategy are targeted on the evaluation and prevention of vascular complications. Acute leukaemia or myelodysplasia, and other clonal progressions like myelofibrotic transformation, are infrequent and delayed events. However, according to the present data, the risk of fibrotic progression or of leukaemic transformation is not related to the mutation status of ET patients.
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PMID:[Essential thrombocythemia. Contribution of the V617F JAK2 mutation to the pathophysiology, diagnosis and outcome]. 1807 52

An acquired somatic mutation in the JAK2 gene (JAK2-V617F) is present in the majority of patients with myeloproliferative disorders (MPDs). Several phenotypic manifestations (polycythemia vera [PV], essential thrombocythemia [ET], and primary myelofibrosis) can be associated with the same mutation. We generated JAK2-V617F transgenic mice using a human JAK2 gene with the sequences encoding the kinase domain placed in the inverse orientation and flanked by antiparallel loxP sites. Crossing mice of one transgenic line (FF1) with transgenic mice expressing Cre-recombinase under the control of the hematopoiesis specific Vav promoter led to expression of JAK2-V617F that was lower than the endogenous wild-type Jak2. These mice developed a phenotype resembling ET with strongly elevated platelet counts and moderate neutrophilia. Induction of the JAK2-V617F transgene with the interferon-inducible MxCre resulted in expression of JAK2-V617F approximately equal to wild-type Jak2 and a PV-like phenotype with increased hemoglobin, thrombocytosis, and neutrophilia. Higher levels of JAK2-V617F in mouse bone marrow by retroviral transduction caused a PV-like phenotype without thrombocytosis. These data are consistent with the hypothesis that the ratio of mutant to wild-type JAK2 is critical for the phenotypic manifestation. A similar correlation was also found in patients with MPD.
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PMID:Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. 1843 61

We report on a bone-marrow biopsy of a 61-year-old female patient that was performed because of the clinical suspicion of a myeloproliferative disease. The trephine biopsy showed morphological features that were consistent with an essential thrombocythaemia (ET). The diagnosis of a myeloproliferative disease could be corroborated by demonstration of the V617F mutation of JAK2. Besides the histological features of ET, the marrow showed a peculiar infiltrate that consisted of multivacuolated cells that were immunohistochemically identified as brown adipose tissue with a hibernoma-like picture. To the best of our knowledge, this is the first report on brown adipose tissue in the bone marrow.
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PMID:Hibernoma-like brown fat in the bone marrow: report of a unique case. 1818 94

Philadelphia chromosome-negative chronic myeloproliferative disorders (Ph(-) CMPD) comprise a group of heterogenous haematological stem cell disorders. These diseases harbour a pathological bone marrow stem cell which overwhelms normal stem cells due to sustained and uncontrolled proliferation. By clonal evolution, acute leukaemia or bone marrow fibrosis evolve in a proportion of cases with as yet unknown underlying mechanisms. Previously, groundbreaking investigations in Ph(-) CMPD detected an acquired mutation in the Janus kinase 2 (JAK2) in the majority of patients with polycythaemia vera (PV) and in up to 50% of patients with essential thrombocythaemia (ET) and chronic idiopathic myelofibrosis (CIMF). Unlike the stem cell defect in Philadelphia chromosome-positive chronic myeloid leukaemia only a subfraction of clonally proliferating haematopoiesis may be affected by the JAK2 mutation. More recently, another mutation in the juxtamembrane domain of the thrombopoietin receptor Mpl was discovered in about 5% of patients with CIMF and ET. In accordance with the uncontrolled Abl kinase activity in Ph(+) chronic myloid leukaemia these mutations in Ph(-) CMPD apparently represent a key to unlock some of the as yet unknown basic molecular defects and this raises hope for an upcoming efficient targeted therapy. However, neither the JAK2(V617F) nor the Mpl(W515L/K) provide the initiating molecular events. Moreover, apart from distinction between reactive and neoplastic lesions, detection of these mutations does not allow a clear-cut discrimination between the particular subtypes. This review will focus on previous and recent findings in the field of molecular defects in Ph(-) CMPD.
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PMID:Stem cell defects in Philadelphia chromosome negative chronic myeloproliferative disorders: a phenotypic and molecular puzzle? 1822 Sep 9

The Janus family of non-receptor tyrosine kinases (JAK1, JAK2, JAK3 and tyrosine kinase 2) transduces signals downstream of type I and II cytokine receptors via signal transducers and activators of transcription (STATs). JAK3 is important in lymphoid and JAK2 in myeloid cell proliferation and differentiation. The thrombopoietin receptor MPL is one of several JAK2 cognate receptors and is essential for myelopoiesis in general and megakaryopoiesis in particular. Germline loss-of-function (LOF) JAK3 and MPL mutations cause severe combined immunodeficiency and congenital amegakaryocytic thrombocytopenia, respectively. Germline gain-of-function (GOF) MPL mutation (MPLS505N) causes familial thrombocytosis. Somatic JAK3 (e.g. JAK3A572V, JAK3V722I, JAK3P132T) and fusion JAK2 (e.g. ETV6-JAK2, PCM1-JAK2, BCR-JAK2) mutations have respectively been described in acute megakaryocytic leukemia and acute leukemia/chronic myeloid malignancies. However, current attention is focused on JAK2 (e.g. JAK2V617F, JAK2 exon 12 mutations) and MPL (e.g. MPLW515L/K/S, MPLS505N) mutations associated with myeloproliferative neoplasms (MPNs). A JAK2 mutation, primarily JAK2V617F, is invariably associated with polycythemia vera (PV). The latter mutation also occurs in the majority of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). MPL mutational frequency in MPNs is substantially less (<10%). In general, despite a certain degree of genotype - phenotype correlations, the prognostic relevance of harbouring one of these mutations, or their allele burden when present, remains dubious. Regardless, based on the logical assumption that amplified JAK-STAT signalling is central to the pathogenesis of PV, ET and PMF, several anti-JAK2 tyrosine kinase inhibitors have been developed and are currently being tested in humans with these disorders.
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PMID:JAK and MPL mutations in myeloid malignancies. 1829 15


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