title: Kinase signaling and targeted therapy for primary myelofibrosis.
abstract: The myeloproliferative neoplasms (MPNs) are somatic mutation-driven hematologic malignancies characterized by bone marrow fibrosis and the accumulation of atypical megakaryocytes with reduced polyploidization in the primary myelofibrosis subtype of the MPNs. Increasing evidence points to a dominant role of abnormal megakaryocytes in disease initiation and progression. Here we review the literature related to kinase signaling pathways relevant to megakaryocyte differentiation and proliferation, including Aurora A kinase, RhoA/ROCK, and JAK/STAT, as well as the activities of their targeted inhibitors in models of the disease. Some of these pathway inhibitors selectively induce megakaryocyte differentiation, suppress malignant proliferation, and promote polyploidization and proplatelet formation. Moreover, combining sets of these inhibitors may be an effective approach to treat and potentially cure MPN patients. For example, preclinical studies reported significant synergistic effects of the combination of an Aurora A inhibitor and JAK1/2 inhibitor, in a murine model of the primary myelofibrosis. Future basic and clinical research into the contributions of these signaling pathways to aberrant megakaryopoiesis may lead to novel effective treatments for MPN patients.
authors.affiliation: Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Northwestern University, Chicago, IL.
authors.forename: John D
authors.initials: JD
authors.lastname: Crispino
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Northwestern University, Chicago, IL. Electronic address: q-wen@northwestern.edu.
authors.forename: Qiang Jeremy
authors.initials: QJ
authors.lastname: Wen
mesh_terms: D000818:Animals; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009218:Myosins / Q000378:metabolism; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011494:Protein Kinases / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D050791:STAT Transcription Factors; D011494:Protein Kinases; D053612:Janus Kinases; D054460:rho-Associated Kinases; D009218:Myosins; D020741:rho GTP-Binding Proteins