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)

The recent discovery of a single point mutation in the JH2 pseudokinase domain of Janus kinase 2 (JAK2) in a considerable fraction of patients has shed light on the molecular pathomechanism in Philadelphia chromosome-negative chronic myeloproliferative disorders (Ph- CMPDs). We established a robust and reliable method for detection of the JAK2 mutation in bone marrow cells derived from archival bone marrow trephines based on polymerase chain reaction and subsequent restriction site analysis. In a series of proven Ph- CMPDs classified according to World Health Organization criteria (n = 79), we detected the JAK2 mutation in 90% of polycythemia vera, 22% of cellular prefibrotic chronic idiopathic myelofibrosis, 60% of advanced chronic idiopathic myelofibrosis, and 27% of essential thrombocythemia. JAK2 mutation was not detected in Ph+ chronic myeloid leukemia (n = 5), acute myeloid leukemia (n = 10), acute lymphoblastic leukemia (n = 10), secondary erythrocytosis (n = 10), or normal bone marrow (n = 10). Restriction site analysis was also suitable for unfixed cell populations derived from peripheral blood and bone marrow aspirates. Besides providing support in the differential diagnosis of reactive versus neoplastic myeloproliferations, this newly developed assay reveals considerable overlaps between histologically different disease entities, indicating that additional genetic alterations might be responsible for the established differences of CMPD subentities.
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PMID:Detection of the single hotspot mutation in the JH2 pseudokinase domain of Janus kinase 2 in bone marrow trephine biopsies derived from chronic myeloproliferative disorders. 1664 2

The suppressor of cytokine signalling-1 (SOCS-1) is a negative regulator of signal transduction mediated by cytoplasmic tyrosine kinases such as the Janus kinases (JAKs). We investigated SOCS-1 expression in bone marrow cells from Philadelphia chromosome negative chronic myeloproliferative disorders (Ph(-) CMPD) and normal haematopoiesis (n=121), and additionally in peripheral blood samples (n=18). Except for chronic idiopathic myelofibrosis harbouring wild-type JAK2, other Ph(-) CMPD expressed significantly higher SOCS-1 levels of up to 14-fold compared to the control group (p<0.001) independent of the JAK2 status. The mononuclear cell fraction but not granulocytes in patients with Polycythaemia vera also significantly overexpressed SOCS-1. We conclude that up-regulation of the SOCS-1 gene might reflect a compensatory feedback mechanism with different emphasis among Ph(-) CMPD subtypes independent of an underlying JAK2 (V617F) mutation.
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PMID:The suppressor of cytokine signalling-1 (SOCS-1) gene is overexpressed in Philadelphia chromosome negative chronic myeloproliferative disorders. 1703 Mar 74

The recently described JAK2 V617F mutation, present in a substantial proportion of nonchronic myelogenous leukemia chronic myeloproliferative disorders (non-CML CMPDs), is changing the way we conceptualize and diagnose these diseases. We hypothesized that the activation of this tyrosine kinase might result in activation of downstream mediators such as STAT5, which would be detectable in bone marrow biopsies. We examined the expression of activated STAT5 (nuclear phospho-STAT5) in 73 bone marrow biopsies from patients with CMPDs [20 essential thrombocythemia (ET), 26 chronic idiopathic myelofibrosis (CIMF), and 27 polycythemia vera] and 39 controls. We compared the results with the JAK2 mutational status and clinical parameters. The frequency of the JAK2 V617F was 73% (85% in PV, 65% in ET, and 65% in CIMF). All patients with the JAK2 V617F showed abnormal nuclear megakaryocytic phospho-STAT5 (nMEG pSTAT5) expression. In the JAK2 wild-type group, nMEG pSTAT5 was observed in 2/7 ET, and 3/9 CIMF patients. nMEG pSTAT5 staining was 100% sensitive and 88% specific for JAK2 V617F. Clinically, nMEG pSTAT5+ patients seemed to require cytoreductive therapy more often than those without nMEG p-STAT expression. pSTAT5 immunohistochemistry is a useful diagnostic test in bone marrow biopsies from suspected non-CML CMPD patients. It identifies most of the patients with the JAK2 V617F but also other JAK2 wild-type CMPD patients. The presence of nMEG pSTAT5 in a subset of CMPD patients lacking the mutation suggests that alternate tyrosine kinase/phosphatase pathways may be involved and warrant further investigation. Phosphoprotein detection represents a new area for diagnostic pathology that exploits specific functional characteristics of cells within the context of a tissue section.
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PMID:Bone marrow phospho-STAT5 expression in non-CML chronic myeloproliferative disorders correlates with JAK2 V617F mutation and provides evidence of in vivo JAK2 activation. 1725 68

Atypical megakaryocytes provide the histomorphological hallmark of all Philadelphia-chromosome negative chronic myeloproliferative disorder (Ph(-) CMPD) subtypes and have not been studied so far for the JAK2(V617F) mutation. The mutant gene dosage was determined in isolated megakaryocytes from 68 cases of JAK2(+)/Ph(-) CMPD by a pyrosequencing assay. Megakaryocytes from essential thrombocythemia (ET) showed significantly lower levels of mutated JAK2 alleles compared to patients with chronic idiopathic myelofibrosis (cIMF) with manifest fibrosis and polycythemia vera (PV) but not to prefibrotic cIMF. Solely, ET JAK2V617F in megakaryocytes is associated with a PV-like phenotype, and at least in one patient, the JAK2 mutation was exclusively acquired within the megakaryocytic lineage. The overt differences between prefibrotic and fibrotic cIMF suggested a causative role of the gene dosage of mutant JAK2 in fibrotic progression. Megakaryocyte analysis of a follow-up of eight individual cases with sequential biopsies, however, showed that progression to homozygosity of V617F mutated JAK2 and onset of manifest fibrosis appeared to be independent events. We conclude that megakaryocytes might be the predominant or even the exclusive lineage that acquires the JAK2(V617F) mutation in ET and that the JAK2(V617F) evolution to higher gene dosages represents a dynamic and complex process substantially involving megakaryocytes.
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PMID:Different involvement of the megakaryocytic lineage by the JAK2 V617F mutation in Polycythemia vera, essential thrombocythemia and chronic idiopathic myelofibrosis. 1726 92

The JAK2 V617F mutation is a frequent genetic event in the three classical Philadelphia-chromosome negative chronic myeloproliferative disorders (Ph(neg.)-CMPD), polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). Its occurrence varies in frequency in regards to phenotype. The mutation is found in the majority of patients with PV and about half of the patients with ET and IMF. These diseases are clonal stem cell disorders arising in an early stem cell progenitor. The level in the stem cell hierarchy on which the initiating genetic events and the JAK2 V617F mutation occurs is not known. The mutation has so far been detected in all cells of the myeloid lineage, whereas the potential clonal involvement of the lymphoid lineage is controversial. In this study, we detected the JAK2 V617F mutation by real-time quantitative PCR (qPCR) in both B-lymphocytes and T-lymphocytes in a subgroup of patients with Ph(neg.)-CMPDs. These results demonstrate the origin of the JAK2 V617F positive disorders in an early stem cell with both lymphoid and myeloid differentiation potential.
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PMID:The JAK2 V617F mutation involves B- and T-lymphocyte lineages in a subgroup of patients with Philadelphia-chromosome negative chronic myeloproliferative disorders. 1731 77

The discovery of the Janus kinase 2 gain-of-function V617F mutation (JAK2(V617F)) provided a major breakthrough in the understanding of Philadelphia chromosome-negative chronic myeloproliferative disorders (Ph(-) CMPD). Among haematologic neoplasm the mutation appears to be almost specific for Ph(-) CMPD but the different entities comprising polycythaemia vera (PV), essential thrombocythaemia and chronic idiopathic myelofibrosis (CIMF) are not discriminated by the mutation. It is unclear how the diversity with heterogeneous clinical and pathoanatomical presentations comes about. It has been suggested that differences in JAK2(V617F) gene dosage or different degrees to which the haematologic lineages are affected by the mutation could explain the heterogeneity of morphology and prognosis. Indeed the mutation mediates a PV-like phenotype but with regard to myelofibrosis JAK2(V617F) does not appear to be a causative factor. Megakaryocytes are homozygous in the majority of fibrotic CIMF and PV, whereas JAK2(V617F) heterozygosity is predominantly encountered in prefibrotic CIMF and essential thrombocythaemia but transition from hetero- to homozygosity with onset of fibrosis is rare. In conclusion, JAK2(V617F) provides a valuable adjunct to the diagnosis of Ph(-) CMPD, in particular with regard to discrimination from reactive proliferations, but the challenge of correct subtyping and hence prognostication persists for clinicians and bone marrow pathologists.
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PMID:Histological and molecular classification of chronic myeloproliferative disorders in the age of JAK2: persistence of old questions despite new answers. 1758 78

Recent observations raise possibility for constitutively active, mutated JAK2 to modulate expression of RAS genes in CMPD. We analyzed the expression of AGT, renin, AT2R1 and ACE genes in normal and bone marrows of PV and ET patients with the respect to the presence of V617F JAK2 mutation. PV and ET had different expression patterns of major RAS components compared to normal BM which was primarily associated with the JAK2V617F mutation and less with PV or ET disease phenotype. However, AT2R1 was exclusively markedly upregulated only in PV, while ET showed moderate expression irrespective of the JAK2 mutational status.
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PMID:Bone marrow renin-angiotensin system expression in polycythemia vera and essential thrombocythemia depends on JAK2 mutational status. 1787 18

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

Patients with Ph chromosome negative myeloproliferative disease (Ph-MPD) have an increased risk of vascular complications. It remains controversial whether patients with the JAK2 V617F mutation (V617F) exhibit increased risk, while recent growing evidence has shown a critical role for V617F in clonal erythropoiesis in Ph-MPD. We studied 53 patients with Ph-MPD especially in relation to megakaryopoiesis, the thrombotic complications and the presence of V617F. Using novel mutation-specific PCR which is a highly sensitive PCR-based assay for detection of JAK2 mutated allele(s), we identified V617F in 38 Ph-MPD, which include 13 polycythemia vera (PV), 23 essential thrombocythemia (ET) and 2 chronic idiopatic myelofibrosis. The numbers of megakaryocytes were significantly increased in PV and ET patients with V617F, but the platelet counts were slightly lower. Although statistically not significant, the incidence of thrombotic events was higher in the group with V617F compared to in those without the mutation. Agonist-induced in vitro platelet aggregation and platelet adhesion were not affected by the presence of this mutation. Nonetheless, we found a hypercoagulable state in Ph-CMPD with V617F by employing whole blood thromboelastography. It suggests pre-thrombotic tendencies in CMPD are complex and JAK2 V617F mutation might have a role in vivo blood coagulation by altering not only the number, but function(s) of all three myeloid cells, including red blood cells, white blood cells and platelets in Ph-CMPD.
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PMID:Megakaryopoiesis and platelet function in polycythemia vera and essential thrombocythemia patients with JAK2 V617F mutation. 1861 78

Patients suffering from Philadelphia chromosome-negative chronic myeloproliferative disease (Ph(-) CMPD), such as polycythaemia vera (PV), are frequently JAK2(V617F)-mutated and have an elevated risk for thromboembolic complications. Recent data indicated that the molecular basis of JAK2(V617F) and thrombosis might be related to increased expression of CD239, the Lutheran blood group/basal cell adhesion molecule, in PV-derived red blood cells. The aim of this study was to clarify whether JAK2(V617F) PV with thromboembolism is characterised by CD239 overexpression. Leukocyte-derived JAK2(V617F) was detectable in bone marrow cells but also in liver and spleen explants and transplants after thrombosis (95% JAK2(V617F)-positive Ph(-) CMPD, n = 66). CD239 was expressed in a constitutive fashion in PV-derived bone marrow cells and thus a pro-thrombotic function does not seem to be mediated by increased CD239 expression alone.
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PMID:Expression of adhesion factor CD239 in bone marrow cells in chronic myeloproliferative diseases. 1897 67


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