Dasatinib enhances megakaryocyte differentiation but inhibits platelet formation.
Posted by rob on March 13, 2011 under Uncategorized | 
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Dasatinib enhances megakaryocyte differentiation but inhibits platelet formation.
Blood. 2011 Mar 8;
Authors: Mazharian A, Ghevaert C, Zhang L, Massberg S, Watson SP
Dasatinib is an oral potent ATP-competitive inhibitor of Bcr-Abl, cKIT and Src family kinases which exhibits good efficacy in patients with Imatinib-resistant chronic myelogenous leukemia. Dasatinib treatment is associated with mild thrombocytopenia and an increased risk of bleeding but its biological effect on megakaryocytopoiesis and platelet production is unknown. In this study, we show that Dasatinib causes mild thrombocytopenia in mice without altering platelet half-life suggesting that Dasatinib inhibits platelet formation. On the other hand, the number of megakaryocytes in bone marrow of Dasatinib-treated mice is increased and the ploidy of megakaryocytes derived from bone marrow progenitor cells in vitro is elevated in the presence of Dasatinib. Furthermore, a significant delay in platelet recovery following immune-induced thrombocytopenia is observed in Dasatinib-treated mice even though the number of megakaryocytes in bone marrow is increased relative to controls at all time points. Interestingly, migration of megakaryocytes towards a gradient of SDF1? and the formation of proplatelets in vitro are abolished by Dasatinib. We propose that Dasatinib causes thrombocytopenia as a consequence of ineffective thrombopoiesis promoting megakaryocyte differentiation on one hand but impairing megakaryocyte migration and proplatelet formation on the other hand.
PMID: 21385851 [PubMed - as supplied by publisher]