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 biologic hallmark of polycythemia vera (PV) is the formation of endogenous erythroid colonies (EECs) with an erythropoietin-independent differentiation. Recently, it has been shown that an activating mutation of JAK2 (V617F) was at the origin of PV. In this work, we studied whether the STAT5/Bcl-xL pathway could be responsible for EEC formation. A constitutively active form of STAT5 was transduced into human erythroid progenitors and induced an erythropoietin-independent terminal differentiation and EEC formation. Furthermore, Bcl-xL overexpression in erythroid progenitors was also able to induce erythroid colonies despite the absence of erythropoietin. Conversely, siRNA-mediated STAT5 and Bcl-xL knock-down in human erythroid progenitors inhibited colony-forming unit-erythroid (CFU-E) formation in the presence of Epo. Altogether, these results demonstrate that a sustained level of the sole Bcl-xL is capable of giving rise to Epo-independent erythroid colony formation and suggest that, in PV patients, JAK2(V617F) may induce EEC via the STAT5/Bcl-xL pathway.
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PMID:Constitutive activation of STAT5 and Bcl-xL overexpression can induce endogenous erythroid colony formation in human primary cells. 1668 63

V617F JAK2 mutation is a reliable molecular marker of polycythemia vera (PV), potentially useful to monitor the effect of treatments in this disease. In a phase 2 study of pegylated (peg) IFN-alpha-2a in PV, we performed prospective sequential quantitative evaluation of the percentage of mutated JAK2 allele (%V617F) by real-time polymerase chain reaction (PCR). The %V617F decreased in 24 (89%) of 27 treated patients, from a mean of 49% to a mean of 27% (mean decrease of 44%; P < .001), and no evidence for a plateau was observed. In one patient, mutant JAK2 was no longer detectable after 12 months. In 3 patients homozygous for the mutation, reappearance of 50% of wild-type allele was observed during treatment. The results seem to confirm the hypothesis that IFN-alpha preferentially targets the malignant clone in PV and show that %V617F assessment using a quantitative method may provide the first tool to monitor minimal residual disease in PV. This trial was registered at www.clinicaltrials.gov as #NCT00241241.
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PMID:High molecular response rate of polycythemia vera patients treated with pegylated interferon alpha-2a. 1670 29

We determined the allelic frequency of the JAK2-V617F mutation in DNA and assessed the expression levels of the mutant and wild-type JAK2 mRNA in granulocytes from 60 patients with essential thrombocythemia (ET) and 62 patients with polycythemia vera (PV) at the time of diagnosis. Using allele-specific quantitative polymerase chain reaction (qPCR), we detected JAK2-V617F in 75% of ET and 97% of PV at diagnosis. The total JAK2 mRNA levels were elevated in ET, PV, and secondary and idiopathic erythrocytosis, suggesting that hyperactive hematopoiesis alters JAK2 expression. The expression levels of JAK2-V617F mRNA were variable but strongly correlated with the allelic ratio of JAK2-V617F determined in DNA. Thus, differences in JAK2-V617F expression, markedly lower in ET than in PV, reflected different percentages of granulocytes carrying the mutation. Moreover, allelic ratios higher than 50% JAK2-V617F, indicating the presence of granulocytes homozygous for JAK2-V617F, were found in 70% of PV at diagnosis but never in ET.
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PMID:The JAK2-V617F mutation is frequently present at diagnosis in patients with essential thrombocythemia and polycythemia vera. 1672 2

JAK2 V617F mutation recently was identified as a pathogenic factor in typical chronic myeloproliferative diseases (CMPD). Some forms of myelodysplastic syndromes (MDS) show a significant overlap with CMPD (classified as MDS/MPD), but the diagnostic assignment may be challenging. We studied blood or bone marrow from 270 patients with MDS, MDS/MPD, and CMPD for the presence of JAK2 V617F mutation using polymerase chain reaction, sequencing, and melting curve analysis. The detection rate of JAK2 V617F mutants for polycythemia vera, chronic idiopathic myelofibrosis, and essential thrombocythemia (n = 103) was similar to the previously reported results. In typical forms of MDS (n = 89) JAK2 V617F mutation was very rare (n = 2). However, a higher prevalence of this mutation was found in patients with MDS/MPD-U (9 of 35). Within this group, most of the patients harboring JAK2 V617F mutation showed features consistent with the provisional MDS/MPD-U entity refractory anemia with ringed sideroblasts and thrombocytosis (RARS-T). Among 9 RARS-T patients, 6 showed the presence of JAK2 V617F mutation, and in 1 patient without mutation, aberrant, positive phospho-STAT5 staining was seen that is typically present in association with JAK2 V617F mutation. In summary, we found that RARS-T reveals a high frequency of JAK2 V617F mutation and likely constitutes another JAK2 mutation-associated form of CMPD.
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PMID:Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2 V617F mutation. 1674 Dec 47

The JAK2(V617F) mutation has been shown to occur in the overwhelming majority of patients with polycythemia vera (PV). To study the role of the mutation in the excessive production of differentiated hematopoietic cells in PV, CD19+, CD3+, CD34+, CD33+, and glycophorin A+ cells and granulocytes were isolated from the peripheral blood (PB) of 8 patients with PV and 3 healthy donors mobilized with G-CSF, and the percentage of JAK2(V617F) mutant allele was determined by quantitative real-time polymerase chain reaction (PCR). The JAK2(V617F) mutation was present in cells belonging to each of the myeloid lineages and was also present in B and T lymphocytes in a subpopulation of patients with PV. The proportion of hematopoietic cells expressing the JAK2(V617F) mutation decreased after differentiation of CD34+ cells in vitro in the presence of optimal concentrations of SCF, IL-3, IL-6, and Epo. These data suggest that the JAK2(V617F) mutation may not provide a proliferative and/or survival advantage for the abnormal PV clone. Although the JAK2(V617F) mutation plays an important role in the biologic origins of PV, it is likely not the sole event leading to PV.
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PMID:Involvement of various hematopoietic-cell lineages by the JAK2V617F mutation in polycythemia vera. 1675 85

An acquired V617F JAK2 mutation occurs in patients with polycythemia vera (PV) or essential thrombocythemia (ET). In a proportion of V617F-positive patients, mitotic recombination produces mutation-homozygous cells that come to predominate with time. However, the prevalence of homozygosity is unclear, as previous reports studied mixed populations of wild-type, V617F-heterozygous, and V617F-homozygous mutant cells. We therefore analyzed 1766 individual hematopoietic colonies from 34 patients with PV or ET in whom granulocyte sequencing demonstrated that the mutant peak did not predominate. V617F-positive erythroid burst-forming units (BFU-Es) were more frequent in patients with PV compared with patients with ET (P = .022) and, strikingly, V617F-homozygous BFU-Es were detected in all 17 patients with PV, but in none of the patients with ET (P < .001). Moreover, mutation-homozygous cells were present in 2 patients with ET after polycythemic transformation. These results demonstrate that V617F-homozygous erythroid progenitors are present in most patients with PV but occur rarely in those with ET.
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PMID:Progenitors homozygous for the V617F mutation occur in most patients with polycythemia vera, but not essential thrombocythemia. 1677 4

The molecular basis of polycythemia vera is discussed in the context of the JAK2 V617F mutation, in our view the most important advance in understanding the pathogenesis of polycythemia vera. This chapter discusses the nature of the JAK2 V617F mutation including the studies demonstrating its role in erythropoietin independence and hypersensitivity and endogenous erythroid colony formation. The evolving evidence that JAK2 V617F is not specific for polycythemia vera pathogenesis and the development of disease phenotype is presented as well as alternative candidates for pathogenic mutations such as the protein tyrosine phosphatases and SOCS-3. Finally, the clinical correlations and implications of the JAK2 V617F mutation are discussed.
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PMID:Polycythemia vera and its molecular basis: an update. 1678 79

Pathogenetically fundamental observations have identified polycythemia vera (PV) as a clonal stem cell disease with bone marrow histological and other biological features that distinctly differentiate it from other causes of 'increased' hematocrit. However, relatively little attention has been given to the effective utilization of pathology and laboratory markers of clonal myeloproliferation as diagnostic tools in PV. In contrast, the diagnostic use of red cell mass (RCM) measurement in PV stemmed from the accidental endorsement, as 'diagnostic criteria', of 'study eligibility criteria' that were formulated for clinical trials. It has since become evident that RCM measurement is a tedious procedure that is fraught with multiple-level imprecision, as well as suboptimal diagnostic accuracy. Therefore, it is reasonable to consider dispensing with RCM measurement as a diagnostic test for PV and instead utilize a diagnostic algorithm that combines clinical information with easily accessible laboratory data, including serum erythropoietin level and bone marrow histology. Recent discoveries of myeloproliferative-disease-specific molecular markers, including the JAK2 V617F tyrosine kinase mutation that is found in the majority of patients with PV, provide further support for such a measure.
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PMID:The diagnosis of polycythemia vera: new tests and old dictums. 1678 83

The clinical criteria according to the Polycythemia Vera Study Group (PVSG) do not distinguish between essential thrombocythemia (ET), thrombocythemia associated with early-stage polycythemia vera (PV) and prefibrotic chronic idiopathic myelofibrosis (CIMF). The criteria only classify the advanced stage of PV with increased red cell mass. The classification of myeloproliferative disorders (MPDs), proposed by the World Health Organization (WHO) in 2001, is a compromise of the clinical PVSG and WHO bone marrow criteria, and excludes early stages of ET and PV. The updated European clinical and pathological criteria combine the WHO bone marrow criteria with established and new clinical, laboratory, biological, and molecular MPD markers. This allows clinicians and pathologists to diagnose early-stage MPD and to differentiate ET, PV, and prefibrotic chronic idiopathic myelofibrosis (CIMF). Depending on laboratory tests and diagnostic criteria used, the population of the MPD patients defined as ET, PV, and CIMF are heterogeneous at the clinical, laboratory, and biological and pathological levels. The recent discovery of the JAK2 V617F mutation, which is the cause of a distinct trilinear MPD in its manifold clinical manifestations during long-term follow-up, increases the specificity of a positive JAK2 V617F polymerase chain reaction (PCR) test for the diagnosis of MPD (near 100%), but only half of the ET and CIMF patients according to the PVSG (sensitivity 50%) and the majority of PV patients (sensitivity 95%) are JAK2 V617F positive. A comparison of the laboratory features of JAK2 V617-positive and JAK2 wild-type ET patients clearly showed that JAK2 V617-positive ET is characterized by higher values for hemoglobin, hematocrit, and neutrophil counts; lower values for serum erythropoietin (EPO) levels, serum ferritin, and mean corpuscular volume; and by increased cellularity of the bone marrow in biopsy material. This indicates that JAK2 V617-positive ET patients, diagnosed according to the PVSG criteria, represent a "forme fruste of PV" consistent with early PV mimicking ET (JAK2 V617F trilinear MPD). In contrast, the JAK2 wild-type ET patients had significantly higher platelet counts and usually had a clinical picture of ET with normal serum EPO levels, PRV-1 expression, and leukocyte alkaline phosphatase score, and a typical WHO ET bone marrow picture. The clinical and pathological data on JAK2 V617F-positive MPD patients suggest that the JAK2 V617F mutation defines one disease entity with several sequential steps of ET, PV, and secondary myelofibrosis during long-term follow-up, and that the wild-type JAK2 MPDs may represent another distinct entity with a related but different molecular etiology. MPD-specific markers such as serum EPO, endogenous erythroid colony formation (EEC), and JAK2 V617F have high specificities, but the sensitivities are not high enough to detect the early stages of the MPDs, ET, PV, and prefibrotic CIMF. Bone marrow histopathology in addition to clinical, laboratory, biological, and molecular markers, including the JAK2 V617 PCR test, serum EPO, PRV-1, EEC, LAP score, peripheral blood parameters, and spleen size on echogram will detect the early stages of MPD and allows diagnostic differentiation of the three primary MPDs (ET, PV, and CIMF) in both JAK2 V617F-positive and JAK2 wild-type MPD patients.
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PMID:The 2001 World Health Organization and updated European clinical and pathological criteria for the diagnosis, classification, and staging of the Philadelphia chromosome-negative chronic myeloproliferative disorders. 1681 Jun 9

The identification of the JAK2 V617F mutation in patients with myeloproliferative disorders (MPDs) represents a major breakthrough in our understanding of the pathogenesis of these diseases. One year after its discovery, an impressive number of publications appeared. These articles confirmed most of the initial results and tried to focus on the main issues arising from this discovery. JAK2 V617F came as recognition of the work of many investigators, starting with William Dameshek, who demonstrated that classical MPDs shared phenotypical mimicry and a general pattern of clinical evolution. We now know that this mutation is the common mark of a molecular clinical entity of MPD shared by 90% of polycythemia vera (PV) and approximately 50% of essential thrombocythemia and idiopathic myelofibrosis patients. However, many questions arise from this discovery. This review, in view of the recent literature, tries to address crucial questions regarding the mechanism of action and the clinical relevance of the JAK2 V617F mutation. The first question is how a unique mutation may explain the clinical diversity of JAK2 V617F-positive MPDs. We now know that acquisition of this mutation is only one step, and that gain of the JAK2 V617F locus, as gain in constitutive Janus kinase 2 (JAK2) activity, may represent another step in disease progression. It is still not known if and how this event or other unknown events may favor disease diversity and possibly disease onset. The second question is how the identification of the JAK2 V617F mutation will change our approach to patients. If detection of JAK2 V617F drastically simplifies the diagnosis of MPDs, and especially PV, prospective clinical trials will be necessary to determine if the therapeutic attitude and disease prognosis will depend on the presence of JAK2 V617F. The third question is how this discovery will benefit the patients. The immediate benefits are still difficult to evaluate, but this discovery, as a major advance in our understanding of the pathogenesis of MPDs, surely has opened perspectives for possible targeted therapies and raises new hopes for patients and clinicians.
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PMID:New insights into the pathogenesis of JAK2 V617F-positive myeloproliferative disorders and consequences for the management of patients. 1681 Jun 10


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