Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0032463 (polycythemia vera)
 3,374 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Exaggerated erythropoiesis and megakaryocytopoiesis are present at a variable extent in polycythemia vera (PV) and essential thrombocythemia (ET). With the recent discovery of the V617F mutation in the Janus kinase 2 (JAK2) tyrosine kinase in almost all cases of PV and in a subset of patients with ET, studies are now pending to assess the role of this mutation in the hematopoietic cell activation process and/or in the occurrence of thromboses in ET and PV. The JAK2 V617F point mutation makes the normal hematopoietic progenitor cells hypersensitive to thrombopoietin, erythropoietin, and myeloid progenitor cells, leading to trilinear hematopoietic myeloproliferation. This will have three main clinical consequences during long-term follow-up. First, spontaneous growth of enlarged mature megakaryocytes in ET/PV with overproduction of hypersensitive platelets results in a broad spectrum of platelet-mediated microvascular circulatory disturbances, which are very sensitive to low-dose aspirin. Second, spontaneous growth of erythropoiesis with the overproduction of erythrocytes leads to classic PV with increased hemoglobin, hematocrit, and red cell mass. This is associated with a high frequency of major arterial and venous thrombotic complications in addition to platelet-mediated microvascular circulatory disturbances of thrombocythemia. Third, the slowly progressive myeloid (granulocytic) metaplasia in bone marrow and spleen is complicated by secondary myelofibrosis caused by a megakaryocytic/granulocytic cytokine storm in about one fourth to one third of JAK2 V617F-positive PV patients after long-term follow-up, with no tendency of leukemic transformation as long as they are not treated with myelosuppressive agents. Randomized clinical trials directly comparing phlebotomy versus hydroxyurea or interferon alpha versus hydroxyurea in PV with progressive disease are lacking. Heterozygous V617F mutation is enough to produce the clinical picture of ET with a slight tendency to increased hemoglobin and hematocrit (early PV mimicking ET). Homozygous V617F mutation is associated with the clinical picture of classic PV and with a higher tendency to secondary myelofibrosis, but with no increased leukemia unless other biological or genetic factors come into play, such as myelosuppressive agents or the acquisition of additional biologic or genetic defects. Depending on the biological background of individual patients, heterozygous and homozygous JAK2 V617F ET/PV may preferentially induce myeloid metaplasia with myelofibrosis with a relative suppression of megakaryocytic and erythropoietic myeloproliferation leading to clinical pictures of fibrotic chronic idiopathic myelofibrosis (CIMF) or agnogenic myeloid metaplasia. The main conclusion is that JAK2 V617F is a 100% specific clue to a new distinct clonal myeloproliferative disorder. JAK2 V617F-positive ET/PV and CIMF should be distinguished from wild-type JAK2 ET, rare cases of PV, and CIMF, and should be evaluated during life-long follow-up.
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PMID:The role of JAK2 V617F mutation, spontaneous erythropoiesis and megakaryocytopoiesis, hypersensitive platelets, activated leukocytes, and endothelial cells in the etiology of thrombotic manifestations in polycythemia vera and essential thrombocythemia. 1681 Jun 14

The selection of treatment for patients with polycythemia vera (PV) still is the subject of much discussion among hematologists. It is emphasized that important physiologic and pathogenic components of the illness relate not only to the erythroid cell, but also to the megakaryocyte. Both play essential roles in causing complications of the disease. Hematologists agree that the mainstay in treatment remains phlebotomy, a basic pillar of the concept of PRIMUM NON NOCERE. In general, the target levels for the hematocrit have been accepted as <or= 45% for men and <or= 42% for women. Low-dose aspirin, 80 to 100 mg daily, should be used as a basic component of therapy. The selection of the type of treatment for those patients who require some form of myelosuppression owing to the frequency of phlebotomy and/or its complications provides the basis for major discussion, confrontation, and disagreement. For the most part, alkylating agents are avoided owing to the established risk of secondary leukemia, but these drugs and radioactive phosphorous ( (32)P) still play a role in treating the very elderly patient or for those who have significant comorbid conditions. Whereas hydroxyurea remains the most frequently prescribed drug, limitations to its use as a therapeutic agent of choice include questions regarding its effectiveness, toxicity, and potential leukemogenicity. Interferon offers a rational choice of treatment owing to its broad physiologic effects on hematopoiesis. Whereas its effect in treating patients with PV is unequivocal, it is associated with side effects even when used properly. Moreover, it has only modest effect on Janus kinase 2 (JAK2) expression. Clearly, the best treatment for patients with PV is still sought. Perhaps more explicit exploitation of the JAK2 abnormality found in PV (and other myeloproliferative diseases) may provide more effective agents in the future.
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PMID:Treatment of polycythemia vera. 1681 Jun 20

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 limited vessel-forming capacity of infused endothelial progenitor cells (EPCs) into patients with cardiovascular dysfunction may be related to a misunderstanding of the biologic potential of the cells. EPCs are generally identified by cell surface antigen expression or counting in a commercially available kit that identifies "endothelial cell colony-forming units" (CFU-ECs). However, the origin, proliferative potential, and differentiation capacity of CFU-ECs is controversial. In contrast, other EPCs with blood vessel-forming ability, termed endothelial colony-forming cells (ECFCs), have been isolated from human peripheral blood. We compared the function of CFU-ECs and ECFCs and determined that CFU-ECs are derived from the hematopoietic system using progenitor assays, and analysis of donor cells from polycythemia vera patients harboring a Janus kinase 2 V617F mutation in hematopoietic stem cell clones. Further, CFU-ECs possess myeloid progenitor cell activity, differentiate into phagocytic macrophages, and fail to form perfused vessels in vivo. In contrast, ECFCs are clonally distinct from CFU-ECs, display robust proliferative potential, and form perfused vessels in vivo. Thus, these studies establish that CFU-ECs are not EPCs and the role of these cells in angiogenesis must be re-examined prior to further clinical trials, whereas ECFCs may serve as a potential therapy for vascular regeneration.
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PMID:Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. 1764 43

Discovery of a constitutively activating point mutation of the Janus kinase 2 (JAK2) receptor-associated tyrosine kinase in patients with polycythemia vera (PV) and other BCR/ABL-negative myeloproliferative disorders prompted many groups around the world to examine diverse subsets of patients with myeloid diseases for the prevalence of the JAK2 V617F mutation and its clinical and pathological associations.
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PMID:MPL W515 and JAK2 V617 mutation analysis in patients with refractory anemia with ringed sideroblasts and an elevated platelet count. 1719 63

The Val617Phe point mutation of Janus kinase 2 gene is believed to participate in the pathogenesis of myeloproliferative syndrome characterised by the clonal alteration of hematopoietic stem cells. According to current results, the frequency of Val617Phe activating mutation is around 80% in polycythaemia vera, 35% in essential thrombocythemia, and 50% in chronic idiopathic myelofibrosis. The diagnoses of polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis were so far based on the exclusion of secondary factors as well as bone marrow biopsy histology. The goal of the present work was to establish simple molecular genetic techniques for the routine testing of Janus kinase 2 gene Val617Phe mutation, and to compare the clinical phenotypes of Val617Phe mutation positive and negative myeloproliferative syndromes. We employed the allele specific polymerase chain technique for detection of Val617Phe mutation in 252 patients with myeloproliferative syndrome. We measured Val617Phe frequency as 85,4% (117/137) in polycythemia vera, 56,6% (56/99) in essential thrombocythemia, and 87,5% (14/16) in idiopathic myelofibrosis. We found significantly elevated hemoglobin levels and white blood cell counts (measured at the time of diagnosis) in Val617Phe-positive polycythemia vera and essential thrombocythemia patient groups compared to Val617Phe-negative patients. However, the frequencies of splenomegaly and other complications (thrombosis, bleeding, transformation to acute leukemia) were not significantly different between the mutation-positive and negative groups. In conclusion, the non-invasive mutation analysis of the Janus kinase 2 Val617Phe is suitable for routine laboratory application and helps the differential diagnosis of myeloproliferative syndrome. Although the exact role of Val617Phe mutation testing has not yet been identified on the basis of a broad professional consensus, the testing is suggested in cases of erythrocytoses and thrombocytoses of unknown origin.
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PMID:[Role of the activating mutation Val617Phe of Janus kinase 2 gene in myeloproliferative diseases and significance of its detection]. 1734 40

The molecular pathogenesis of chronic myeloproliferative disorders (MPDs) is poorly understood. The hematopoietic progenitor cells of patients with polycythemia vera (PV) or essential thrombocythemia (ET) are characterized by hypersensitivity to hematopoietic growth factors and formation of endogenous erythroid colonies. Recently, 4 groups reported almost simultaneously Janus kinase 2 (JAK2) V617F mutation in more than 80% of PV patients, 30% of patients with ET and in about 50% of patients with idiopathic myelofibrosis. The identification of the JAK2 mutation represents a major advance in the understanding of the molecular pathogenesis of MPDs that will likely permit a new classification and the development of novel therapeutic strategies for these diseases.
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PMID:Pathogenetic role of JAK2 V617F mutation in chronic myeloproliferative disorders. 1738 52

Three sets of diagnostic criteria for polycythaemia vera (PV); the Polycythaemia Vera Study Group (PVSG) criteria (1975), the British Committee for Standards in Haematology (BCSH) criteria (1996) and the World Health Organisation (WHO) criteria (2001) have been described. We compared the ability of each set of criteria to accurately diagnose PV and differentiate it from secondary, apparent and idiopathic erythrocytosis. A cohort was drawn from a clinical database of erythrocytosis patients currently attending the Belfast City Hospital and the relevant information from the time of diagnosis for each patient was assessed according to each set of criteria, with the BCSH criteria used as a comparator. Sufficient data was available on 71 patients: 46 PV, 8 idiopathic, 8 apparent and 9 secondary erythrocytosis. The BCSH criteria classified 34 of 46 patients (73.9%) as PV and the WHO criteria had a sensitivity and specificity of 100% for classifying PV. For idiopathic and apparent erythrocytosis, the specificity of the WHO criteria, compared to the BCSH criteria, declined to 66.7 and 87.5%, respectively. The PVSG criteria were limited by the unavailability of required data for some patients resulting in a sensitivity and specificity of 50% for PV and specificity of 100% for all other groups. The Janus kinase 2 (JAK2) V617F mutation was present in 34 (85.3%) PV, 2 (50%) IE, 1 (50%) apparent and no secondary erythrocytosis cases. We concluded that the BCSH criteria were the most accurate diagnostic criteria for PV as they had an acceptable level of sensitivity and could differentiate between PV and other erythrocytoses.
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PMID:Comparison of diagnostic criteria for polycythaemia vera. 1745 93

The Janus kinase 2 mutation, JAK2617V>F, is myeloid neoplasm-specific; its presence excludes secondary polycythemia, thrombocytosis, or bone marrow fibrosis from other causes. Furthermore, JAK2617V>F or a JAK2 exon 12 mutation is present in virtually all patients with polycythemia vera (PV), whereas JAK2617V>F also occurs in approximately half of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Therefore, JAK2 mutation screening holds the promise of a decisive diagnostic test in PV while being complementary to histology for the diagnosis of ET and PMF; the combination of molecular testing and histologic review should also facilitate diagnosis of ET associated with borderline thrombocytosis. Accordingly, revision of the current World Health Organization (WHO) diagnostic criteria for PV, ET, and PMF is warranted; JAK2 mutation analysis should be listed as a major criterion for PV diagnosis, and the platelet count threshold for ET diagnosis can be lowered from 600 to 450 x 10(9)/L. The current document was prepared by an international expert panel of pathologists and clinical investigators in myeloproliferative disorders; it was subsequently presented to members of the Clinical Advisory Committee for the revision of the WHO Classification of Myeloid Neoplasms, who endorsed the document and recommended its adoption by the WHO.
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PMID:Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. 1822 75


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