Non-Driver Genomic Alterations and Venous Thromboembolism in Myeloproliferative Neoplasms
Helen AjufoAvi LeaderAndriy DerkachPavlina ChrysafiRohan Kumar SinghRaajit K. RampalSimon ManthaJeffrey I. Zwicker
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Myeloproliferative Disorders
Myeloproliferative neoplasms are clonal hematopoietic disorders that manifest as expansion of one or more myeloid lineages. The most common myeloproliferative neoplasms are chronic myeloid leukemia (CML), polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Whereas the genetic basis for CML has been known for more than 30 years, the specific genetic events that contribute to the pathogenesis of polycythemia vera, essential thrombocythemia, and primary myelofibrosis remained unknown until 2005.Our first insight into the molecular cause of these disorders came when the somatic JAK2 V617F mutation14 was identified in the majority of patients with polycythemia vera and in a subset . . .
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The chronic myeloproliferative disorders, polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are clonal stem cell disorders that occur at a low frequency and mimic not only each other clinically, but also many benign and malignant hematopoietic disorders as well. The discovery that many patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis express a mutation in the Janus Kinase 2 gene (JAK2 V617F), a kinase essential for the normal development of erythrocytes, granulocytes, and platelets, provided a molecular explanation for the unregulated hematopoiesis typical of these disorders, a diagnostic test that distinguishes them from other types of myeloproliferative disorders, and an opportunity to develop targeted therapy that could potentially avoid the toxicities associated with the conventional chemotherapeutic agents currently employed in their treatment. In this review, we discuss the molecular basis of polycythemia vera, essential thrombocythemia, and primary myelofibrosis, their diagnosis and their management in the context of the JAK2 V617F mutation.
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Abstract Accurate distinction between essential thrombocythemia and thrombocytotic polycythemia vera requires determination of the red cell mass in the presence of adequate iron stores, but this is not always possible. We therefore compared the clinical and laboratory features at the time of presentation of 50 patients with unequivocal essential thrombocythemia and 27 patients with thrombocytotic polycythemia vera. Univariate analysis failed to identify any single parameter capable of reliably separating the groups. A logistic regression algorithm incorporating hematocrit, white cell count, and spleen size markedly increased the diagnostic accuracy (92 %) compared with predictions based on the hematocrit alone (52 %). The algorithm's usefulness for patients with intermediate hematocrits was confirmed by analysis of independent samples of essential thrombocythemia and thrombocytotic polycythemia vera patients, and also by analysis of patients with probable essential thrombocythemia in whom the diagnosis could not be confirmed because of inadequate exclusion of polycythemia vera. Furthermore, comparison of survival data suggests that differentiating these disorders is prognostically important. The algorithm is recommended as an alternate method for differentiating essential thrombocythemia from thrombocytotic polycythemia vera whenever the red cell mass is unavailable or iron deficiency cannot be excluded.
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Background: In 2005, multiple groups identified a high frequency of the V617F (G→T) mutation in the tyrosine kinase gene JAK2 in myeloproliferative neoplasms. In this study, we evaluated prevalence of JAK2 mutation and it’s clinical and laboratory correlates in patients with myeloproliferative neoplasms (MPNs).
Methods: The JAK2 mutation was investigated with ARMS-PCR in 92 patients with myeloproliferative neop-lasms by simple randomized sampling.
Findings: The JAK2 V617F mutation was detected in 86.6% (26/30) of patients with polycythemia vera, 46.6% (7/15) of patients with essential thrombocythemia, 61.5% (8/13) of patients with idiopathic myelofibrosis, and 14% (4/34) of patients with chronic myeloid leukemia. Polycythemia vera patients carrying the mutation dis-played a higher levels of WBC (P = 0.03); 61.5% (16/26) of these patients were female and 17 patients had sple-nomegaly. One patient had simultaneously JAK2 V617F mutation and Philadelphia chromosome. The differences in other groups were not significant. The mutation was confirmed by sequencing.
Conclusion: These correlations imply that detection of this mutation will not only have a diagnostic value, but also a role in treatment given the development of STAT/JAK pathway inhibiting drugs.
Keywords: JAK2 V617F mutation, myeloproliferative neoplasms, ARMS-PCR.
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This issue of Seminars in Thrombosis and Hemostasis extends the discussion on myeloproliferative disorders (MPDs) from the previous issue, focusing on diagnosis, staging, and management of these patients.
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We analyzed the effect of hydroxyurea on the JAK2V617F allelic ratio (%JAK2V617F), measured in purified blood granulocytes, of patients with polycythemia vera and essential thrombocythemia. Thirty-six patients were examined sequentially prior to and after start of hydroxy-urea therapy (8 polycythemia vera, 17 essential thrombocythemia), or while remaining untreated (2 polycythemia vera, 9 essential thrombocythemia). Hydroxyurea therapy (median duration: 15 months) reduced the %JAK2V617F by >30% in 13/25 patients (4 polycythemia vera, 9 essential thrombocythemia). For 3 patients, JAK2V617F remained undetectable for 3-27 months. In addition, a single time point study of two large cohorts of patients, examined either at the time of diagnosis (99 polycythemia vera, 178 essential thrombocythemia) or while receiving hydroxyurea (36 polycythemia vera, 98 essential thrombocythemia; median length of therapy: 32 months), confirmed reduction of %JAK2V617F in the hydroxyurea-treated group (24% vs. 33% JAK2V617F at diagnosis, p<0.01). Prospective studies are needed to determine the prognostic value of reduced JAK2V617F allele burden under cytoreductive therapy.
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The study was designed to investigate the influence of hydroxyurea (HU) treatment on PRV-1 expression. Eighteen newly diagnosed patients with essential thrombocythemia (ET) or polycythemia vera (PV) were included. HU significantly increased PRV-1 gene expression in the early stage of treatment.
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