Effects of the Sympathicomimetic Agonist Mirabegron on Disease Course, Mutant Allele Burden, Marrow Fibrosis, and Nestin Positive Stem Cell Niche in Patients with JAK2-Mutated Myeloproliferative Neoplasms. a Prospective Multicenter Phase II Trial SAKK 33/14
Beatrice DrexlerJakob PasswegMartin BiglerAlexandre TheocharidesNathan CantoniPeter M. KellerGeorg StuessiAxel RüferRudolf BenzGeneviève FavreAlexandar TzankovPontus LundbergAndrea FuhrerChristine BiaggiMarkus G. ManzMario BargetziSimón Méndez‐FerrerRadek C. Skoda
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Myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are clonal, progressive, hematological malignancies resulting in the risk of vascular events, splenomegaly, and significant symptom burden, with a high prevalence of fatigue.[
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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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Polycythemia vera, essential thrombocythemia and primary myelofibrosis are currently classified as myeloproliferative neoplasms and represent a stem cell-derived clonal myeloproliferation. Current diagnosis is made according to the 2008 World Health Organization classification system that utilizes both bone marrow histology and molecular markers. Recent information has revealed the presence of JAK2 and MPL mutations in the majority of patients with these disorders. Accordingly, the therapeutic value of anti-JAK2 drugs is currently being investigated.
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Megakaryocytes are the "hallmark" of Philadelphia chromosome-negative myeloproliferative neoplasms, such as essential thrombocythemia, polycythemia vera, and primary myelofibrosis; their morphology in correlation with Janus kinase 2 (JAK2 V617F) mutation as well as clinical and laboratory parameters remains unknown.To assess the morphology of megakaryocytes in bone marrow biopsies of patients with and without JAK2 V617F mutation.Assessment of morphologic features of megakaryocytes in 112 bone marrow biopsies (52 essential thrombocythemia, 38 polycythemia vera, and 22 primary myelofibrosis) and correlation with clinical and laboratory data.JAK2 V617F mutation was detected in 24 of 52 essential thrombocythemia cases (46.2%), 36 of 38 polycythemia vera cases (97.5%), and 14 of 22 primary myelofibrosis cases (63.6%). By investigating morphometric and clinical parameters using multivariate analysis, we found that higher hemoglobin concentration, higher white blood cell counts, and lower platelet counts were significantly associated with JAK2 V617F. Striking morphologic similarities were found between polycythemia vera JAK2 V617F and primary myelofibrosis JAK2 V617F concerning the localization and cytoplasmic size of megakaryocytes. Although polycythemia vera JAK2 V617F and essential thrombocythemia JAK2 V617F shared similarities in localization, distribution, and amount of megakaryocytes, morphology was different. Megakaryocytic morphology also differed between primary myelofibrosis JAK2 V617F and essential thrombocythemia JAK2 V617F.Our results indicate that primary myelofibrosis JAK2 V617F and polycythemia vera JAK2 V617F share pathogenetic pathways, resulting in morphologically similar megakaryocytes.
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