Narrative Review: Thrombocytosis, Polycythemia Vera, and JAK2 Mutations: The Phenotypic Mimicry of Chronic Myeloproliferation

Johns Hopkins Medical Institutions, Baltimore, Maryland 21205-2196, USA.
Annals of internal medicine (Impact Factor: 17.81). 03/2010; 152(5):300-6. DOI: 10.1059/0003-4819-152-5-201003020-00008
Source: PubMed


The myeloproliferative disorders polycythemia vera, essential thrombocytosis, and primary myelofibrosis are clonal disorders arising in a pluripotent hematopoietic stem cell, causing an unregulated increase in the number of erythrocytes, leukocytes, or platelets, alone or in combination; eventual marrow dominance by the progeny of the involved stem cell; and a tendency to arterial or venous thrombosis, marrow fibrosis, splenomegaly, or transformation to acute leukemia, albeit at widely varying frequencies. The discovery of an activating mutation (V617F) in the gene for JAK2 (Janus kinase 2), a tyrosine kinase utilized by hematopoietic cell receptors for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor, provided an explanation for the shared clinical features of these 3 disorders. Constitutive JAK2 activation provides a growth and survival advantage to the hematopoietic cells of the affected clone. Because signaling by the mutated kinase utilizes normal pathways, the result is overproduction of morphologically normal blood cells, an often indolent course, and (in essential thrombocytosis) usually a normal life span. Because the erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor receptors are all constitutively activated, polycythemia vera is the potential ultimate clinical phenotype of the JAK2 V617F mutation and, as a corollary, is the most common of the 3 disorders. The number of cells expressing the JAK2 V617F mutation (the allele burden) seems to correlate with the clinical phenotype. Preliminary results of clinical trials with agents that inhibit the mutated kinase indicate a reduction in splenomegaly and alleviation of night sweats, fatigue, and pruritus.

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    • "A prominent example of such a condition is polycythemia vera. Polycythemia vera (PV) is a chronic myeloproliferative neoplasm, characterized by increased red cell mass and is often accompanied by thrombocytosis and leukocytosis131415. The clinical course of the disease can be complicated by both thrombotic and hemorrhagic events which remain the leading causes of morbidity and mortality in untreated PV patients [15,16] . "
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    ABSTRACT: Using patients with polycythemia vera (PV) as an experimental model, we evaluated the impact of clot retraction (CR) and architecture of the clot on fibrinolysis. We studied the kinetics of clot retraction and the fibrinolysis rate in whole blood from 48 PV patients and 48 healthy controls. Measurements were performed before and after isovolemic eryhrocytapheresis (ECP). CR was measured by optical method. Clot lysis time (CLT) and maximum clot firmness (MCF) were measured by thromboelastometry in recalcified blood supplemented with t-PA and tissue factor. Compared with healthy controls, CR rate in PV patients was higher (0.0219 vs. 0.0138; p < 0.001), the clot volume smaller and MCF elevated (64 vs. 58 mm). CR rate correlated with platelet count (r = 0.546; p = 0.001) but not with erythrocyte concentration (r = 0.192; p > 0.3). Compared with healthy controls, CLT in PV patients was significantly prolonged (158 min vs. 71 min). Fibrinolysis rate inversely correlated with CR rate (r = -0.566; p < 0.001); MCF (r = -0.704; p < 0.001) and platelet count (r = -0.461; p < 0.001). As judged by confocal microscope, in comparison to healthy controls, clots formed in blood from PV patients demonstrated booth a distinctly higher degree of crosslinking and possessed thinner fibers. Altered CR, MCF and fibrinolysis speeds were not normalized following the ECP procedure. Tirofiban (a blocker of platelet GPIIb/IIIa receptors), unlike aspirin, normalized abnormal CR and fibrinolysis in blood from PV patients. Collectively, our data indicate that in PV patients, abnormal CR may result in formation of thrombi that are more resistant to fibrinolysis. ECP and aspirin failed to normalize platelet-related fibrinolysis resistance.
    Full-text · Article · Jul 2014 · Thrombosis Research
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    • "Signaling involved in the effects of growth hormone include janus-activated kinase-2 JAK2 [21] [22], which contributes to effects of several further hormones and cytokines [23] [24] [25], such as leptin [25], erythropoietin [25], thrombopoietin [25] and granulocyte colony-stimulating factor [25]. Excessive JAK2 activity may lead to the development of malignancy and JAK2 inhibitors are considered for the treatment of myeloproliferative disorders [26] [27] [28] [29] [30] [31]. "
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    ABSTRACT: Background: Na(+) coupled phosphate transporter NaPiIIa is the main carrier accomplishing phosphate transport across the apical cell membrane of proximal renal tubules and thus renal tubular phosphate reabsorption. The carrier is regulated by a wide variety of hormones and cellular signaling molecules. Hormones stimulating renal tubular phosphate transport and thus leading to hyperphosphatemia include growth hormone. Signaling of growth hormone involves activation of janus-activated kinase-2 JAK2, which has previously been shown to participate in the regulation of several Na(+) coupled transporters. Experiments exploring the effect of JAK2 on phosphate transport have, however, never been reported. The present study thus addressed the effect of JAK2 on NaPiIIa. Methods: cRNA encoding NaPiIIa was injected into Xenopus oocytes with or without additional injection of cRNA encoding wild type JAK2, the gain of function mutant JAK2(V617F) or inactive JAK2(K882E). Phosphate-induced current (I(NaPi)) reflecting electrogenic phosphate transport was determined by two electrode voltage clamp. Moreover, NaPiIIa protein abundance in the cell membrane was determined by chemiluminescence. Results: No appreciable I(NaPi) was observed in water injected oocytes or in oocytes expressing JAK2 alone. In NaPiIIa expressing oocytes I(NaPi) was significantly increased by additional expression of JAK2 or JAK2(V617F), but not by coexpression of JAK2(K882E). In oocytes expressing both, NaPiIIa and JAK2, I(NaPi) was gradually decreased by JAK2 inhibitor AG490 (40 μM). Coexpression of NaPiIIa and JAK2 or JAK2(V617F), but not of JAK2(K882E) increased NaPiIIa protein abundance in the cell membrane. Disruption of carrier protein insertion with Brefeldin A (5 μM) was followed by a decline of I(NaPi) to a similar extent in Xenopus oocytes expressing NaPiIIa with JAK2 and in Xenopus oocytes expressing NaPiIIa alone, suggesting that JAK2 did not affect carrier stability in the cell membrane. Conclusion: JAK2 contributes to the regulation of phosphate transporter NaPiIIa.
    Full-text · Article · Jan 2013 · Biochemical and Biophysical Research Communications
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    • "G-banded chromosome analysis (bone marrow) revealed an abnormal 46,XY, t(9;22)(p24;q11.2)[18]/46,XY [[2]] karyotype; an apparently balanced translocation between the short arm of one chromosome 9 and the long arm of one chromosome 22, which was detected in 90 % of metaphases analyzed. "
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    ABSTRACT: Translocation (9;22)(q34;q11.2) resulting in BCR/ABL1 fusion at the molecular level is the hallmark of chronic myelogenous leukemia (CML). Variants of the Philadelphia translocation and complex translocations involving BCR have been reported in myeloproliferative disorders (MPD). A rare translocation, t(9;22)(p24;q11.2), resulting in a novel BCR-JAK2 fusion has been reported in a handful of cases of CML and acute myelogenous leukemia (AML). We present clinical-pathological and cytogenetic evaluation of a patient with Philadelphia-chromosome negative CML/MPD harboring a t(9;22)(p24;q11.2) resulting in BCR-JAK2 fusion. Fluorescence in situ hybridization and molecular characterization of the translocation confirmed a BCR-JAK2 fusion and helped delineate the breakpoints upstream of exon 1 of minor cluster region of BCR gene and likely intron 18 of the JAK2 gene, resulting in an in-frame transcript This case provides convincing support, along with two previous case-reports, for a role for activation of the Janus kinase 2 in evolution of myeloproliferative disease. The recurrent, albeit rare, nature of the breakpoints within BCR and JAK2 suggests a potential new diagnostic target that should be interrogated in Ph-negative CML/MPD patients.
    Full-text · Article · May 2012 · Molecular Cytogenetics
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