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)

A single acquired mutation in the JAK2 gene has recently been described in human myeloproliferative disorders, including most patients with polycythemia vera and about half of those with essential thrombocythemia and idiopathic myelofibrosis. Reliable and easily implemented methods for detection of this V617F mutation promise to revolutionize the way these disorders are diagnosed and classified, and may in the future have implications for targeted therapeutics. Two polymerase chain reaction-based methods for detection of the mutation are described here. One method is based on allele-specific amplification of the mutant band, and the other on elimination of a restriction enzyme recognition sequence by the mutation. Both methods are significantly more sensitive than conventional sequencing techniques, and could be readily implemented in a molecular diagnostic laboratory.
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PMID:Methods for the detection of the JAK2 V617F mutation in human myeloproliferative disorders. 1650 90

JAK2(V617F)an acquired mutation of JAK2, is present in a majority of patients with polycythemia vera and to a lesser extent among patients with the other myeloproliferative disorders. We analyzed the effect of JAK2(V617F) on the expression of polycythemia rubra vera 1(PRV-1), using an in vitro model. Compared to wild-type JAK2, the presence of JAK2(V617F) increased both PRV-1 protein and mRNA levels in murine myeloid cells. A JAK2 inhibitor eliminated the V617F-induced increase in PRV-1 expression.
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PMID:The effect of the JAK2 V617F mutation on PRV-1 expression. 1650 46

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

Signal transducer and activator of transcription (STAT) proteins are phosphorylated and activated by Janus kinases (JAKs). Recently, several groups identified a recurrent somatic point mutation constitutively activating the hematopoietic growth factor receptor-associated JAK2 tyrosine kinase in diverse chronic myeloid disorders - most commonly classic myeloproliferative disorders (MPD), especially polycythemia vera. We hypothesized that the JAK2 V617F mutation might also be present in samples from patients with acute myeloid leukemia (AML), especially erythroleukemia (AML-M6) or megakaryoblastic leukemia (AML-M7), where it might mimic erythropoietin or thrombopoietin signaling. First, we documented STAT3 activation by immunoblotting in AML-M6 and other AML subtypes. Immunoperoxidase staining confirmed phosphorylated STAT3 in malignant myeloblasts (21% of cases, including all AML-M3 samples tested). We then analyzed genomic DNA from 162 AML, 30 B-cell lymphoma, and 10 chronic lymphocytic leukemia (CLL) samples for JAK2 mutations, and assayed a subset for SOCS1 and FLT3 mutations. Janus kinase2 V617F was present in 13/162 AML samples (8%): 10/13 transformed MPD, and three apparent de novo AML (one of 12 AML-M6, one of 24 AML-M7, and one AML-M2 - all mixed clonality). FLT3 mutations were present in 5/32 (16%), while SOCS1 mutations were totally absent. Lymphoproliferative disorder samples were both JAK2 and SOCS1 wild type. Thus, while JAK2 V617F is uncommon in de novo AML and probably does not occur in lymphoid malignancy, unexplained STAT3 activation is common in AML. Janus kinase2 extrinsic regulators and other proteins in the JAK-STAT pathway should be interrogated to explain frequent STAT activation in AML.
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PMID:JAK2 V617F is a rare finding in de novo acute myeloid leukemia, but STAT3 activation is common and remains unexplained. 1659 6

Although a large proportion of patients with polycythemia vera (PV) harbor a valine-to-phenylalanine mutation at amino acid 617 (V617F) in the JAK2 signaling molecule, the stage of hematopoiesis at which the mutation arises is unknown. Here we isolated and characterized hematopoietic stem cells (HSC) and myeloid progenitors from 16 PV patient samples and 14 normal individuals, testing whether the JAK2 mutation could be found at the level of stem or progenitor cells and whether the JAK2 V617F-positive cells had altered differentiation potential. In all PV samples analyzed, there were increased numbers of cells with a HSC phenotype (CD34+CD38-CD90+Lin-) compared with normal samples. Hematopoietic progenitor assays demonstrated that the differentiation potential of PV was already skewed toward the erythroid lineage at the HSC level. The JAK2 V617F mutation was detectable within HSC and their progeny in PV. Moreover, the aberrant erythroid potential of PV HSC was potently inhibited with a JAK2 inhibitor, AG490.
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PMID:The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation. 1660 27

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

A JAK2(V617F) mutation is frequently found in several BCR/ABL-negative myeloproliferative disorders. To address the contribution of this mutant to the pathogenesis of these different myeloproliferative disorders, we used an adoptive transfer of marrow cells transduced with a retrovirus expressing JAK2(V617F) in recipient irradiated mice. Hosts were analyzed during the 6 months after transplantation. For a period of 3 months, mice developed polycythemia, macrocytosis and usually peripheral blood granulocytosis. Transient thrombocytosis was only observed in a low-expresser group. All mice displayed trilineage hyperplasia in marrow and spleen along with an amplification of myeloid and erythroid progenitor cells and a formation of endogenous erythroid colonies. After 3 to 4 months, polycythemia regressed, abnormally shaped red blood cells and platelets were seen in circulation, and a deposition of reticulin fibers was observed in marrow and spleen. Development of fibrosis was associated with anemia, thrombocytopenia, high neutrophilia, and massive splenomegaly. These features mimic human polycythemia vera and its evolution toward myelofibrosis. This work demonstrates that JAK2(V617F) is sufficient for polycythemia and fibrosis development and offers an in vivo model to assess novel therapeutic approaches for JAK2(V617F)-positive pathologies. Questions remain regarding the exact contribution of JAK2(V617F) in other myeloproliferative disorders.
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PMID:JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis. 1667 Feb 66

Microvascular disturbances in essential thrombocythemia (ET) and polycythemia vera (PV), including erythromelalgia, and atypical and typical transient cerebral, ocular, and coronary ischemic attacks, are caused by platelet-mediated transient and occlusive thrombosis in the end-arterial circulation. ET patients with microvascular disturbances have shortened platelet survival, increased beta-thromboglobulin (beta-TG), platelet factor 4 (PF4), and thrombomodulin (TM) levels, and increased urinary thromboxane B2 (TXB2) excretion, indicating platelet-mediated thrombotic processes. Inhibition of platelet cyclooxygenase-1 by aspirin is followed by relief of microvascular disturbances; correction of shortened platelet survival; correction of increased plasma beta-TG, PF4, and TM levels; and correction of increased TXB2 excretion to normal. In PV associated with thrombocythemia, increased hematocrit and whole blood viscosity aggravate the platelet-mediated microvascular syndrome of thrombocythemia to produce major arterial and venous thrombotic complications. Correction of hematocrit to normal by phlebotomy will reduce the major arterial and venous thrombotic complications, but fails to prevent the platelet-mediated microvascular circulation disturbances in PV patients because thrombocythemia persists. Complete relief and prevention of microvascular and major thrombosis in ET and PV patients, in addition to phlebotomy, are obtained by treatment with aspirin and not with coumarin. The discovery of JAK2 V617F gain of function mutation in patients with myeloproliferative disorders (MPDs) expands our insights into the molecular etiology and biological features of ET, PV, and chronic idiopathic myelofibrosis (CIMF). The current concept is that heterozygous JAK2 V617F mutation with increased kinase activity is enough for megakaryocyte proliferation and increased hypersensitive platelets with no or slightly increased erythropoiesis in ET and in early PV mimicking ET. Homozygous JAK2 mutation with pronounced kinase activity is associated with trilinear megakaryocyte, erythroid, and granulocytic myeloproliferation, myeloid metaplasia, and secondary myelofibrosis (MF), with the most frequent clinical picture of classical PV complicated by major thrombosis in addition to the platelet-mediated microvascular thrombotic syndrome of thrombocythemia. The positive predictive value of a JAK2 V617F polymerase chain reaction test for the diagnosis of MPDs is high (near to 100%), but only half of ET and MF (sensitivity 50%) and the majority of PV (sensitivity 85 to 97%) are JAK2 V617F positive. Bone marrow histopathology, when used in combination with specific markers such as serum erythropoietin, PRV-1, endogenous erythroid colony formation, peripheral blood parameters and red cell mass, has a high sensitivity and specificity (near 100%) to detect the early and overt stages of the MPDs and to differentiate between ET, PV, and CIMF in both JAK2 V617F-positive and -negative MPDs.
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PMID:Clinical and laboratory features, pathobiology of platelet-mediated thrombosis and bleeding complications, and the molecular etiology of essential thrombocythemia and polycythemia vera: therapeutic implications. 1667 74

Formation of endogenous erythroid colonies (EECs) or endogenous megakaryocytic colonies (EMCs) is a hallmark of myeloproliferative disorders (MPDs). The diagnostic value of EEC for polycythemia vera (PV) using standardized media has been demonstrated, and has led clinicians to consider EEC as a major diagnostic criterion in the WHO classification. The interest of EEC currently needs to be considered taking into account recent data about V617F JAK2 mutation in MPD. In particular, EECs and EMCs should be helpful for the diagnostic and the vascular risk evaluation of essential thrombocythemia (ET) and for mutation negative patients. A low serum erythropoietin (EPO) level is a consistent finding in PV. Recent studies have shown that commercial serum EPO assays provided a reliable, accurate, and low-cost criterion for the diagnosis of a significant proportion of PV. It suggests that diagnostic algorithms integrating serum EPO level could be elaborated. The diagnostic value of EPO assay for thrombocytosis has not been proved, but some data suggest a predictive value of low EPO levels for thrombosis in ET.
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PMID:Influence of the assays of endogenous colony formation and serum erythropoietin on the diagnosis of polycythemia vera and essential thrombocythemia. 1667 78

Polycythemia vera (PV) is a hematopoietic stem cell disorder characterized by a predominant proliferation of the erythroid cell line. The diagnosis is commonly based on the WHO criteria. The acquired V617F mutation in the tyrosine kinase gene JAK2 represents a new molecular marker proving clonality in PV and other chronic myeloproliferative disorders. Phlebotomy is still the treatment of choice to reduce the red cell mass. Low-dose acetylsalicylic acid is successful in the primary prophylaxis of vascular complications. However, the majority of patients require myelosuppressive therapy during the course of their disease due to progressive myeloproliferation. Hydroxyurea still plays a role in patients of all age groups. Interferon alpha represents an alternative, particularly for younger patients. Apart from sporadic cases of bone marrow transplantation, there is no known curative treatment in PV. To date, the diagnosis of PV was based mainly on clinical criteria. The identification of the JAK2 mutation enables new approaches to the diagnosis, classification, and treatment of PV and of the other myeloproliferative disorders.
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PMID:Diagnosis and therapy of polycythemia vera. 1667 81


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