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)

We report the emergence of a chronic myeloid leukaemia (CML) during the course of a JAK2V617F-positive chronic idiopathic myelofibrosis (CIMF) in the absence of any myelosuppressive treatment. Although a response to imatinib was observed, the underlying myelofibrosis persisted after treatment and hydroxyurea was finally added to control the persistent thrombocytosis. Such rare patients with co-existing BCR-ABL translocation and JAK2V617F mutation must be identified in view of the possibility of targeted therapies. Moreover, the detection of BCR-ABL translocation appears to be crucial especially in the case of treated CIMF with an atypical course to identify CML before acute transformation.
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PMID:Emergence of therapy-unrelated CML on a background of BCR-ABL-negative JAK2V617F-positive chronic idiopathic myelofibrosis. 1843 74

Abnormal nuclear megakaryocytic staining for phospho-STAT5 (pSTAT5) correlates with JAK2 V617F mutational status in non-chronic myelogenous leukemia chronic myeloproliferative disorders. However, a proportion of wild-type JAK2 non-chronic myelogenous leukemia chronic myeloproliferative disorders cases also demonstrate this abnormal pSTAT5 expression pattern. We report a patient with a JAK2 V617F-negative myeloproliferative/myelodysplastic syndrome who had abnormal megakaryocytic pSTAT5 expression and a MPL W515L mutation. The patient was a 71-year-old man with anemia and thrombocythemia on laboratory examination. His peripheral blood smear demonstrated occasional dysplastic neutrophils. Bone marrow biopsy revealed hypercellular marrow with features consistent with myeloproliferative/myelodysplastic syndrome. Immunohistochemistry for pSTAT5 showed abnormal nuclear megakaryocyte positivity. Cytogenetic analysis revealed a normal karyotype, fluorescence in situ hybridization for BCR-ABL was negative, and JAK2 genotyping demonstrated wild-type JAK2. However, MPL genotyping showed a MPL W515L mutation. Abnormal nuclear megakaryocytic staining for pSTAT5 expression, previously associated with the JAK2 V617F mutation, is also associated with MPL W515L, likely reflecting activation of the JAK-STAT signaling pathway.
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PMID:Phospho-STAT5 expression pattern with the MPL W515L mutation is similar to that seen in chronic myeloproliferative disorders with JAK2 V617F. 1847 30

Familial chronic myeloproliferative disorders are defined when in the same pedigree at least two relatives have a chronic myeloproliferative disorder (CMD) as polycythemia vera (PV), essential thrombocythemia (ET) or primary myelofibrosis (PMF). This condition should be distinguished from inherited disorders with Mendelian transmission and single haematopoietic lineage proliferation, named hereditary erythrocytosis and thrombocytosis. The recently discovered mutations in patients with CMD (V617F and exon 12 of JAK2 gene, MPL gene), and those identified in hereditary erythrocytosis and in hereditary thrombocytosis have improved our ability to discriminate these conditions. In familial CMD, the JAK2 mutations are acquired and occur as secondary genetic events. As both mutations of the JAK2 gene have been reported in the same pedigree, a genetic predisposition to the acquisition of the JAK2 mutations is supposed to be inherited. The prevalence of familial cases within CMD is at least 7.6%. The inheritance pattern of familial CMD is consistent with an autosomal dominant trait with decreased penetrance. The clinical presentation at diagnosis of patients with familial CMD does not differ from that of patients with sporadic CMD. In addition, patients with familial CMD develop the same type of complications (thrombosis and haemorrhage) and disease evolution (post-PV myelofibrosis, post-ET myelofibrosis and leukaemia) observed in patients with sporadic CMD. The 10-year survival is 83% for patients with familial PV, 100% for those with familial ET, and 30% for those with familial PMF. The aim of this review is to focus the state of the art of familial CMD and to offer an overview of inherited conditions causing erythrocytosis and thrombocytosis.
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PMID:Familial chronic myeloproliferative disorders: the state of the art. 1848 77

Essential thrombocythemia (ET) is a chronic myeloproliferative disorder, characterized by increased proliferation of megakaryocytes and elevated platelet count that usually occurs sporadically. We report a family with seven affected individuals in three generations, including one individual with a phenotype resembling polycythemia vera, a related disorder. Megakaryocyte (CFU-MK) colony formation occurred in the absence of added cytokines in cultures of peripheral blood from affected family members. Some reports of familial ET have identified mutations in THPO and MPL, the genes for a cytokine (thrombopoietin, TPO) that regulates platelet production and its receptor (c-MPL), respectively. In this family, the MPL gene was excluded by linkage analysis. Although TPO levels were elevated in most affected family members and evidence for linkage was found between the disease and THPO (theta=0.0, Z(max)=3.0), a THPO mutation was not identified by DNA sequencing. The JAK2 V617F mutation that has been associated with 50% of sporadic cases of ET was identified as a somatic mutation, an acquired defect, in peripheral blood of the two most severely affected family members. These patients also had elevated TPO levels. Further study of familial myeloproliferative diseases will help elucidate the initiating genetic events underlying ET.
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PMID:Familial essential thrombocythemia with spontaneous megakaryocyte colony formation and acquired JAK2 mutations. 1849 61

We describe the management of a patient with a femoral fracture who had asymptomatic essential thrombocythemia. When the diagnosis of essential thrombocythemia was made, the patient was treated with plateletpheresis to reduce the platelet count before intramedullary rod fixation of his fracture. His postoperative management included the examination of his peripheral blood as well as bone marrow, which confirmed that the cause of his elevated platelet count was due to JAK2 V617F mutation that is treated by hydroxyurea and aspirin after being discharged from the hospital.
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PMID:Management of femoral fracture in a patient with essential thrombocythemia treated with plateletpheresis and intramedullary rod fixation, followed by hydroxyurea: a case report. 1853 15

The V617F mutation of JAK2 is the key molecular event in 90% of polycythaemia vera (PV), 50% of essential thrombocythaemia (ET) and 50% of primary myelofibrosis (PMF). JAK2 exon 12 and MPLW515 mutations are less frequent. Because JAK2 V617F is specific for myeloid neoplasms, and because it can be detected in peripheral blood granulocytes, it offers a powerful tool that facilitates the diagnosis of these BCR-ABL negative myeloproLiferative disorders. These discoveries provide the rationale for a revision of the current WHO diagnostic criteria for PV, ET and PMF and could ultimately lead to the development of a specific targeted therapy.
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PMID:Clinical implications of JAK2 mutations in myeloproliferative disorders. 1857 49

Several sensitive methods for the detection of JAK2 V617F mutation have been published recently, most of them based on Real Time polymerase chain reaction (PCR). However, only some of them have performed studies of diagnostic validity. This study compares three methods based on Real Time PCR to detect JAK2 V617F mutation: two based on hybridization probes (HP) and peptide nucleic acid probe (PNA) and a third employing allele specific oligonucleotide primers for JAK2 V617F quantification. One hundred forty-nine healthy subjects, 61 essential thrombocythemia (ET), 32 polycythemia vera (PV), 38 secondary thrombocytoses, and 35 secondary erythrocytoses were included. Validity test study for JAK2 617 HP PCR in PV Sensitivity (Se) was 88% and in Specificity (Sp), 100%. In ET, Se was 57% and Sp, 100%. For JAK2 617 PNA PCR in PV, Se was 94% and Sp, 97.8%. In ET, Se was 70% and Sp, 95.7%. In JAK2 V671F allelo-specific-oligonucleotide (ASO) quantitative PCR (qPCR), cutoff point of 1% was established by receiving operating characteristic (ROC) curves. In PV, Se was 93.8% and Sp, 98.5%. In ET, Se was 80% and Sp, 95.9%. Two percent of the healthy subjects were positive by JAK2 617 PNA PCR and 2% by JAK2 617 ASO qPCR. JAK2 V617F mutation was detected in healthy subjects by cloning and sequencing. JAK2 617 HP is an adequate test in differential diagnosis for both erythrocytosis and thrombocytosis. When JAK2 V617F allele burden is low, JAK2 617 ASO qPCR should be performed. Simultaneous determination of JAK2 V617F and PRV-1 overexpression does not improve the diagnostic value of JAK2 V617F tests in MPD.
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PMID:Validity test study of JAK2 V617F and allele burden quantification in the diagnosis of myeloproliferative diseases. 1857 65

To elucidate the role of thrombocytosis, alone or in combination with standard (age, previous cardiovascular events) and novel (leukocytosis, JAK2(V617F) mutational status) risk factors, in the cardiovascular events of essential thrombocythemia (ET), we analyzed a cohort of 1063 patients. We found that a platelet count at diagnosis greater than 1000 x 10(9)/L was associated with significantly lower rate of thrombosis in multivariable analysis and, if combined with leukocytes less than 11 x 10(9)/L, pointed to a "low-risk" category with a rate of thrombosis of 1.59% of patients/year. On the contrary, the highest risk category (thrombosis rate, 2.95% of patients/year) was constituted of patients with leukocytosis, lower platelet count, and a JAK2(V617F) mutated genotype in most cases (77% vs 26% in the low-risk group), independently from standard risk factors. These data challenge the theory that elevated platelet count increases thrombosis risk in ET and suggest prospective clinical trials to support this hypothesis.
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PMID:Thrombocytosis and leukocytosis interaction in vascular complications of essential thrombocythemia. 1884 Jul 27

Approximately half of the patients with essential thrombocythaemia (ET) harbor the JAK2 V617F mutation. Despite a phenotypic mimicry of JAK2 V617F positive ET and polycythaemia vera (PV), the data on thromboembolic risk and correlation to JAK2 mutation status are ambiguous. On a strictly WHO defined ET cohort we evaluated possible clinical correlations to the JAK2 mutation status including a history of previous thrombosis. We used a highly sensitive quantitative real-time PCR (qPCR) assay for JAK2 V617F detection and allele burden quantification in a single institution study of 55 patients. A significantly increased prevalence of arterial thrombosis was recorded in JAK2 positive ET (p=0.001). There was no association between the mutational load and thrombosis. As compared to their JAK2 V617F negative counterparts, the JAK2 V617F positive patients had PV-like biochemical characteristics such as higher haemoglobin levels (p=0.02), lower platelet counts (p=0.002) and lower plasma EPO levels (p=0.04). The JAK2 V617F mutation per se but not the mutational load in patients with ET is associated with a PV-like phenotype and a higher prevalence of previous arterial thrombosis. This study adds further support to the contention of the JAK2 V617F mutation as a marker of increased risk of thrombosis.
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PMID:High prevalence of arterial thrombosis in JAK2 mutated essential thrombocythaemia: independence of the V617F allele burden. 1861 71

The objective of this study was to validate the recently revised 2008 WHO diagnostic criteria of myeloproliferative neoplasms (MPN) together with the analysis of correlation of JAK2 (Janus kinase 2)-V617F mutant allele burden with clinical/laboratory findings on each patient. We made a diagnosis of 75 suspected MPN patients based on both diagnostic criteria of the 2001 WHO classification and the revised 2008 WHO classification, and found that both criteria show a quite similar diagnostic power except for two patients (idiopathic erythrocytosis (IE) and thrombocytosis) who were diagnosed as essential thrombocythemia by the 2008 WHO criteria. From JAK2-V617F analysis, hemoglobin and hematocrit values were significantly higher and platelet count was lower in JAK2-V617F high allele burden group than JAK2-V617F middle allele burden group. Mutant allele burden of polycythemia vera (PV) group was higher than that of essential thrombocythemia group. Therefore, the amount of mutant allele seemed to define the disease phenotypes. We further found a PV case presenting a rare type of JAK2-exon12 mutation. In contrast, IE presented a good prognosis unlike MPN. Hereafter, the 2008 WHO criteria with JAK2 gene analysis are useful for precise diagnosis of MPN and the patients with erythrocytosis.
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PMID:Validation of the revised 2008 WHO diagnostic criteria in 75 suspected cases of myeloproliferative neoplasm. 1879 95


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