Distinct Clinical Phenotypes Associated with JAK2V617F Reflect Differential STAT1 Signaling
Edwin ChenPhilip BeerAnna L. GodfreyChristina A. OrtmannJuan LiAna P. Costa‐PereiraCatherine IngleEmmanouil T. DermitzakisPeter J. CampbellAnthony R. Green
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STAT1
STAT5
Myeloproliferative Disorders
Janus kinase 2
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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The myeloproliferative disorders comprise a group of related diseases, including polycythemia vera, essential thrombocythemia, chronic myelogenous leukemia, myelofibrosis, and myeloid metaplasia. An increase in circulating platelets is associated with thrombotic phenomena affecting the arterial and venous circulation. In this article, the authors describe a case in which the initial manifestation of myeloproliferative disease was gangrene of the fingers.
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The discovery of an identical mutation (V617F) of the JAK2 gene in patients with polycythemia vera, essential thrombocythemia, and myelofibrosis — the principal Philadelphia chromosome–negative myeloproliferative disorders — has greatly advanced our understanding of these conditions. This article reviews the legacy of this discovery and how it has changed our view of the origins, interrelations, and management of the myeloproliferative disorders.
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A family of latent cytoplasmic transcription factors, signal transducers and activators of transcription (STATs), mediates the responsiveness of cells to several cytokines and growth factors. Although mutations of STATs have not been described in human tumors, the activity of several members of the family, such as STAT1, STAT3 and STAT5, is deregulated in a variety of human tumors. STAT3 and STAT5 acquire oncogenic potential through constitutive phosphorylation on tyrosine, and their activity has been shown to be required to sustain a transformed phenotype. Disruption of STAT3 and STAT5 signaling in transformed cells therefore represents an excellent opportunity for targeted cancer therapy. In contrast to STAT3 and STAT5, STAT1 negatively regulates cell proliferation and angiogenesis and thereby inhibits tumor formation. Consistent with its tumor suppressive properties, STAT1 and its downstream targets have been shown to be reduced in a variety of human tumors and STAT1 deficient mice are highly susceptible to tumor formation. In recent years we have gained mechanistic understanding of the pathways whereby STATs convey signals from the cytoplasm to the nucleus. In addition, several endogenous regulators of the JAK/STAT pathway have been described - and their mechanism of action revealed - that profoundly affect signaling by STATs. Both should greatly facilitate the design of drugs with potential to modulate STAT signaling and to restore the homeostasis in tissues where STATs have gone awry.
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This article focuses on the rapidly evolving understanding of the molecular pathogenetic mechanisms of the bcr-abl-negative myeloproliferative neoplasms (MPN) [myeloproliferative disorders (MPD)], such as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (MF). The amplify therapies were reviewed and IFN-α is an effective agent for these MPN (MPD). Also, the article emphasize once again avoidance MPN and select MPD for such chinese patients.
Key words:
Myeloproliferative neoplasms, MPN; Myeloproliferative disorders, MPD; JAK2 V617F gene mutation; Interferon-alpha
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