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

Jerry L. Spivak, MD
[+] Article and Author Information

From the Johns Hopkins Medical Institutions, Baltimore, Maryland.


Grant Support: From the National Institutes of Health (P01CA108671).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M09-1012.

Requests for Single Reprints: Jerry L. Spivak, MD, Hematology Division, Johns Hopkins University School of Medicine, Traylor Building, Room 924, 720 Rutland Avenue, Baltimore, MD 21205-2196; e-mail, jlspivak@jhmi.edu.


Ann Intern Med. 2010;152(5):300-306. doi:10.7326/0003-4819-152-5-201003020-00008
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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.

Figures

Grahic Jump Location
Figure.
The close interrelationship among the chronic myeloproliferative disorders, and a schematic representation of hematopoietic stem-cell commitment and JAK2 utilization.

Top. The chronic myeloproliferative disorders not only are phenotypically similar but can also evolve into each other. From a clinical perspective, as illustrated isolated thrombocytosis of unknown cause should not automatically be assumed to be essential thrombocytosis because isolated thrombocytosis can also be the presenting manifestation of polycythemia vera or primary myelofibrosis. Bottom. JAK2 is an obligatory kinase primarily for erythroid and megakaryocytic cell development; granulocytes can also use JAK1, and lymphocytes do not require JAK2. As illustrated, polycythemia vera is the ultimate clinical phenotype that can be caused by constitutive JAK2 activation.

Grahic Jump Location

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