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)

An activating JAK2 mutation (JAK2 V617F) is present in the chronic myeloproliferative disorders (MPDs), polycythemia vera (PV), idiopathic myelofibrosis (IMF), and essential thrombocytosis (ET). JAK2 is also a chaperone for Mpl and responsible for its cell-surface expression. We observed a reciprocal relationship between neutrophil JAK2 V617F allele percentage and platelet Mpl expression in JAK2 V617F-positive PV, IMF, and ET patients. However, severely impaired platelet Mpl expression was present in JAK2 V617F-negative MPD patients. While JAK2 V617F allele status did not necessarily correlate with the clinical MPD phenotype, the degree of impaired platelet Mpl expression did. We conclude that multiple molecular abnormalities are involved in the pathogenesis of the MPDs and that aberrant Mpl expression may be a common denominator of aberrant signaling in both the JAK2 V617F-positive and JAK2 V617F-negative MPDs.
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PMID:Molecular mimicry in the chronic myeloproliferative disorders: reciprocity between quantitative JAK2 V617F and Mpl expression. 1691 29

The clinical criteria for the diagnosis of essential thrombocythemia (ET) according to the polycythemia vera study group (PVSG) do not distinguish between ET and thrombocythemia associated with early stage PV and prefibrotic chronic idiopathic myelofibrosis (CIMF). The clinical criteria of the PVSG for the diagnosis of polycythemia vera (PV) only detects advanced stage of PV with increased red cell mass. The bone marrow criteria of the World Health Organization (WHO) are defined by pathologists to explicitly define the pathological criteria for the diagnostic differentiation of ET, PV, and prefibrotic and fibrotic CIMF. As the clinical PVSG and the pathological WHO criteria show significant shortcomings, an updated set of European Clinical and Pathological (ECP) criteria combined with currently available biological and molecular markers are proposed to much better distinct true ET from early PV mimicking ET, to distinguish ET from thrombocythemia associated with prefibrotic CIMF, and to define the various clinical and pathological stages of PV and CIMF that has important therapeutic and prognostic implications. Comparing the finding of clustered giant abnormal megakaryocytes in a representative bone marrow as a diagnostic clue to MPD, the sensitivity for the diagnosis of MPD associated with splanchnic vein thrombosis was 63% for increased red cell mass, 52% for low serum EPO level, 72% for EEC, and 74% for splenomegaly indicating the superiority of bone marrow histopathology to detect masked early and overt MPD in this setting. The majority of PV and about half of the ET patients have spontaneous EEC, low serum EPO levels and PRV-1 over-expression and are JAK2 V617F positive. The positive predictive value for the diagnosis of PV of spontaneous growth of endogenous erythroid colonies (EEC) of peripheral blood (PB) and bone marrow (BM) cells is about 80-85% when either PB or BM EEC assays, and up to 94% when BM and PB EEC assays were performed. The diagnostic impact of low serum EPO levels (ELISA assay) in a large study of 186 patients below the normal range (<3.3 IU/l) had a sensitivity specificity and positive predictive value of 87%, 97% and 97.8%, respectively, for the diagnosis of PV. There is a significant overlap of serum EPO levels in PV versus control and controls versus SE. The specificity of a JAK2 V617F PCR test for the diagnosis of MPD is high (near 100%), but only half of ET and MF (50%) and the majority of PV (up to 97%) are JAK2 V617F positive. The use of biological markers including JAK2 V617 PCR test, serum EPO, PRV-1, EEC, leukocyte alkaline phosphatase score and peripheral blood parameters combined with bone marrow histopathology has a high sensitivity and specificity (almost 100%) to diagnose the early and overt stages of ET, PV and CIMF in JAK2 V617F positive and negative MPDs.
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PMID:Current diagnostic criteria for the chronic myeloproliferative disorders (MPD) essential thrombocythemia (ET), polycythemia vera (PV) and chronic idiopathic myelofibrosis (CIMF). 1691 93

The classical myeloproliferative disorders (MPDs) are comprised of the clonal, BCR-ABL-negative, chronic myeloid disorders of essential thrombocythemia, polycythemia vera, and myelofibrosis with myeloid metaplasia. Management of these disorders remains a significant challenge due to the varied range of prognosis and phenotypic manifestations. Curative therapy, achieved in some patients through allogeneic stem cell transplantation, is elusive or inappropriate in most. Additionally, no available medical therapy has been shown to clearly improve survival or delay disease progression. Current management involves an emphasis on prevention of thrombohemorrhagic complications (through aspirin treatment, phlebotomy and cytoreduction in high-risk patients) in early-stage patients and symptomatic care in those with advanced disease. Leukemic transformation from MPDs remains a rapidly fatal complication, unresponsive to current therapies. Recent elucidation of the role of the activating tyrosine kinase mutation JAK2 (V617F) is anticipated to usher in an era of greater understanding and targeted therapy for the MPDs.
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PMID:Practical management of classical myeloproliferative disorder patients: a clinician's guide. 1692 18

One hundred and forty four patients with a clinical indication of suspected polycythemia vera (PV), essential thrombocythemia, or idiopathic myelofibrosis were screened for JAK2(V617F) and the mutation frequency was 47, 51, and 50%, respectively. Previous investigations enabled 42 of 66 patients with suspected PV to be definitively diagnosed either as PV according to WHO criteria or to have this diagnosis excluded. Ninety-six percent of those with PV were JAK2(V617F), whereas all patients without PV did not have the mutation. Early screening of suspected PV patients for JAK2(V617F) rapidly identifies nearly all those with PV without invasive or less specific conventional investigations.
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PMID:Identification of JAK2V617F in patients with polycythemia is highly correlated with conventional criteria for diagnosis of polycythemia vera. 1692 38

A retrospective investigation of the JAK2 V617F mutation was carried out in DNA samples from 131 bone marrow (BM) core biopsy specimens corresponding to patients with polycythemia vera (PV) (n = 31), essential thrombocythemia (ET) (n = 31), chronic idiopathic myelofibrosis (CIM) (n = 18), as well as patients with normal BM and secondary reactive hyperplasia. We used the TaqMan polymerase chain reaction single nucleotide polymorphism genotyping assay to detect the specific JAK2 mutation. This technique allowed us to detect the JAK2 V617F mutation in a population containing at least 5% of homozygous mutants. Overall, the incidence of the JAK2 V617F mutation was 87% in PV, 67% in ET, and 66% in CIM. This approach proved to be reliable and more sensitive in detecting the mutation compared with that of initial studies on different materials but similar to that of recent work with various polymerase chain reaction-based techniques. Two essential findings arose from our study. First, this technique could be carried out with DNA samples, even partially degraded, from routinely processed BM core biopsy specimens. Second, after correlation with morphological features, it turned out that the characteristics of the megakaryocytes were more specific than the mutational status of JAK2 in characterizing ET and CIM. Concerning PV, as expected, the incidence of the JAK2 mutation was higher, but the morphological criteria were misleading in some cases, strongly suggesting that the combination of both histologic and molecular data would enable the characterization of virtually all cases.
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PMID:Frequent detection of the JAK2 V617F mutation in bone marrow core biopsy specimens from chronic myeloproliferative disorders using the TaqMan polymerase chain reaction single nucleotide polymorphism genotyping assay: a retrospective study with pathologic correlations. 1788 78

The molecular basis of chronic idiopathic myelofibrosis (CIMF) has remained elusive, thus hampering the development of effective targeted therapies. However, significant progress regarding the molecular mechanisms involved in the pathogenes is of this disease has been made in recent years that will likely provide ample opportunity for the investigation of novel therapeutic approaches. At the fore front of these advances is the discovery that 35%-55% of patients with CIMF harbor mutations in the Janus kinase 2 tyrosine kinase gene. Until very recently, the management of patients with CIMF involved the use of supportive measures, including growth factors, transfusions, or interferon, and the administration of cyto-reductive agents, such as hydroxyurea and anagrelide. However, several trials have demonstrated the efficacy of antiangiogenic agents alone or in combination with corticosteroids. In addition, the use of reduced-intensity conditioning allogeneic stem cell transplantation has resulted in prolonged survival and lower transplant-related mortality.
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PMID:Advances in the therapy of chronic idiopathic myelofibrosis. 1695 97

The JAK2 V617F mutation has recently been described as an essential oncogenic event associated with polycythemia vera (PV), idiopathic myelofibrosis (IMF), and essential thrombocythemia. This mutation has been detected in all myeloid lineages but has not yet been detected in lymphoid cells. This raises the question whether this molecular event occurs in a true lymphomyeloid progenitor cell. In this work, we studied the presence of the mutation in peripheral blood cells and sorted B, T, and natural killer (NK) cells from PV and IMF. We detected the JAK2 V617F mutation in B and NK cells in approximately half the patients with IMF and a minority of those with PV. Moreover, in a few cases patients with IMF had mutated peripheral T cells. The mutation (homozygous or heterozygous) could be subsequently detected in B/NK/myeloid progenitors from PV and IMF, with a much higher frequency in clones derived from IMF. Using the fetal thymus organ culture (FTOC) assay, the mutation was also detected in all T-cell fractions derived from IMF and PV CD34+ cells. These results demonstrate that myeloproliferative disorders take their origin in a true myeloid/lymphoid progenitor cell but that their phenotype is related to a downstream selective proliferative advantage of the myeloid lineages.
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PMID:Evidence that the JAK2 G1849T (V617F) mutation occurs in a lymphomyeloid progenitor in polycythemia vera and idiopathic myelofibrosis. 1695 6

This study was aimed at the characterization of a gene expression signature of the pluripotent hematopoietic CD34(+) stem cell in idiopathic myelofibrosis (IM), which would eventually provide novel pathogenetic insights and/or diagnostic/prognostic information. Aberrantly regulated genes were revealed by transcriptome comparative microarray analysis of normal and IM CD34(+) cells; selected genes were also assayed in granulocytes. One-hundred seventy four differentially expressed genes were identified and in part validated by quantitative polymerase chain reaction. Altered gene expression was corroborated by the detection of abnormally high CD9 or CD164, and low CXCR4, membrane protein expression in IM CD34(+) cells. According to class prediction analysis, a set of eight genes (CD9, GAS2, DLK1, CDH1, WT1, NFE2, HMGA2, and CXCR4) properly recognized IM from normal CD34(+) cells. These genes were aberrantly regulated also in IM granulocytes that could be reliably differentiated from control polycythemia vera and essential thrombocythemia granulocytes in 100% and 81% of cases, respectively. Abnormal expression of HMGA2 and CXCR4 in IM granulocytes was dependent on the presence and the mutational status of JAK2(V617F) mutation. The expression levels of both CD9 and DLK1 were associated with the platelet count, whereas higher WT1 expression levels identified IM patients with more active disease, as revealed by elevated CD34(+) cell count and higher severity score. In conclusion, molecular profiling of IM CD34(+) cells uncovered a limited number of genes with altered expression that, beyond their putative role in disease pathogenesis, are associated with patients' clinical characteristics and may have potential prognostic application.
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PMID:Molecular profiling of CD34+ cells in idiopathic myelofibrosis identifies a set of disease-associated genes and reveals the clinical significance of Wilms' tumor gene 1 (WT1). 1699 May 84

Diagnosis of the myeloproliferative disorders, polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF) is difficult due to lack of diagnostic markers. Recently, the acquisition of a mutation in the Janus kinase 2 (JAK2) gene by hemopoietic cells has been described as a genetic defect underlying myeloproliferative disorders. The mutation leads to constitutive activation of JAK2, a tyrosine kinase involved in cytokine receptor signalling. Because of the clinical importance of this mutation (JAK2 V617F) in diagnosing myeloproliferative disorders and its relevance for disease progression, we developed a semi-quantitative real-time PCR test to detect JAK2 V617F. With this assay, quantities down to 0.8% JAK2 V617F amongst wild-type DNA could reliably be detected. For quantification purposes, low intra- and inter-assay variabilities ensure good reproducibility of the assay. Thus the JAK2 V617F qPCR assay described here is quick, robust, simple and more sensitive than direct sequencing, RFLP, ARMS assay and other methods published so far to detect JAK2 V617F. We therefore believe that the assay will contribute to early diagnosis of myeloproliferative disorders and to disease management, especially when JAK2-specific inhibitors have become available for therapeutic use.
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PMID:A sensitive and reliable semi-quantitative real-time PCR assay to detect JAK2 V617F in blood. 1700 61

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


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