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.

37 Reads
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    Biochemical and Biophysical Research Communications 01/2013; 431(2). DOI:10.1016/j.bbrc.2012.12.137 · 2.30 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Molecular Cytogenetics 05/2012; 5(1):23. DOI:10.1186/1755-8166-5-23 · 2.14 Impact Factor
  • Source
    • "JAK2 inhibitors are being tested in ET, but their benefits are unclear. It is not known if they will impact on progression or survival.(31) "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic myeloproliferative diseases without the Philadelphia chromosome marker (Ph-), although first described 60 years ago, only became the subject of interest after the turn of the millennium. In 2001, the World Health Organization (WHO) defined the classification of this group of diseases and in 2008 they were renamed myeloproliferative neoplasms based on morphological, cytogenetic and molecular features. In 2005, the identification of a recurrent molecular abnormality characterized by a gain of function with a mutation in the gene encoding Janus kinase 2 (JAK2) paved the way for greater knowledge of the pathophysiology of myeloproliferative neoplasms. The JAK2 mutation is found in 90-98% of polycythemia vera and in about 50% essential thrombocytosis and primary myelofibrosis. In addition to the JAK2 mutation, other mutations involving TET2 (ten-eleven translocation), LNK (a membrane-bound adaptor protein); IDH1/2 (isocitrate dehydrogenase 1/2 enzyme); ASXL1 (additional sex combs-like 1) genes were found in myeloproliferative neoplasms thus showing the importance of identifying molecular genetic alterations to confirm diagnosis, guide treatment and improve our understanding of the biology of these diseases. Currently, polycythemia vera, essential thrombocytosis, myelofibrosis, chronic neutrophilic leukemia, chronic eosinophilic leukemia and mastocytosis are included in this group of myeloproliferative neoplasms, but are considered different situations with individualized diagnostic methods and treatment. This review updates pathogenic aspects, molecular genetic alterations, the fundamental criteria for diagnosis and the best approach for each of these entities.
    03/2012; 34(2):140-9. DOI:10.5581/1516-8484.20120034
Show more


37 Reads
Available from