الفهرس 
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Abstract
Major progress has been recently made in understanding the molecular pathogenesis of myeloproliferative neoplasms (MPN). Mutations in one of four genes−JAK2, MPL, CALR, and CSF3R−can be found in the vast majority of patients with MPN and represent driver mutations that can induce the MPN phenotype. Hyperactive JAK/STAT signaling appears to be the common denominator of MPN, even in patients with CALR mutations and the so-called ‘‘triple-negative’’ MPN, where the driver gene mutation is still unknown.
Mutations in epigenetic regulators, transcription factors, and signaling components modify the course of the disease and can contribute to disease initiation and/or progression. The central role of JAK2 in MPN allowed development of small molecular inhibitors that are in clinical use and are active in almost all patients with MPN. Advances in understanding the mechanism of JAK2 activation open new perspectives of developing the next generation of inhibitors that will be selective for the mutated forms of JAK2. Driver mutations in MPN are now formally integrated into the WHO diagnostic criteria for polycythemia vera (98% JAK2 mutational frequency), essential thrombocythemia (60% JAK2, 22% CALR and 3% MPL mutational frequency) and primary myelofibrosis (58% JAK2, 25% CALR and 7% MPL). These clonal markers are now effectively used to distinguish MPN from secondary/reactive erythrocytosis or thrombocytosis.
In its most recent (2016) revision the WHO document lists the presence of driver mutations as one of several major criteria in the diagnosis of PV, ET and PMF.
Essential thrombocythemia and polycythemia vera are among the Philadelphia chromosome negative myeloproliferative neoplasms. They are characterized by over production of blood cells and their complications include thrombosis, hemorrhage, and progression to myelofibrosis or acute myeloid leukemia (AML). Management of essential thrombocythemia/polycythemia vera requires recognition of the risk factors for thrombosis and hemorrhage. Risk stratification allows the clinician to make a treatment plan that may include antiplatelet therapy with aspirin alone or in combination with therapeutic phlebotomy in the case of polycythemia vera, or cytoreductive therapy for high-risk patients with either essential thrombocythemia or polycythemia vera. Hydroxyurea remains first-line therapy for high-risk patients with essential thrombocythemia/polycythemia vera, whereas second-line options include anagrelide, pegylated- IFNa-2a, and the JAK1/2 inhibitor ruxolitinib. The current evaluation of pegylated-IFNa-2a in global phase II and III studies will provide clarity to the potential long-term benefit and risks associated with this biologic in patients with essential thrombocythemia/polycythemia vera.
Novel therapeutics aimed at prevention of disease progression to myelofibrosis/AML are the focus of current clinical trials.
Myelofibrosis (MF) is a myeloproliferative neoplasm that presents either as a primary disease or evolves secondarily from polycythemia vera or essential thrombocythemia to post–polycythemia vera MF or post– essential thrombocythemia MF, respectively.
Therapeutic options for patients with MF have been limited to the use of cytoreductive agents, predominantly hydroxyurea, erythropoiesis-stimulating agents, androgens, and immunomodulatory agents along with steroids. The only curative option is allogeneic stem cell transplantation (ASCT), which is associated with high morbidity and mortality risks. Recently, JAK (Janus kinase) inhibitor therapies have become available and proven to be palliative in primary MF patients with hydroxyurea refractory splenomegaly and severe constitutional symptoms.