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首页> 外文期刊>Blood: The Journal of the American Society of Hematology >Dasatinib enhances megakaryocyte differentiation but inhibits platelet formation.
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Dasatinib enhances megakaryocyte differentiation but inhibits platelet formation.

机译：达沙替尼可增强巨核细胞分化，但可抑制血小板形成。

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摘要

Dasatinib is a novel, potent, ATP-competitive inhibitor of Bcr-Abl, cKIT, and Src family kinases that exhibits 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 it inhibits platelet formation. Conversely, the number of megakaryocytes (MKs) in the bone marrow of dasatinib-treated mice was increased and the ploidy of MKs derived from bone marrow progenitor cells in vitro was elevated in the presence of dasatinib. Furthermore, a significant delay in platelet recovery after immune-induced thrombocytopenia was observed in dasatinib-treated mice even though the number of MKs in the bone marrow was increased relative to controls at all time points. Interestingly, the migration of MKs toward a gradient of stromal cell-derived factor 1alpha (SDF1alpha) and the formation of proplatelets in vitro were abolished by dasatinib. We propose that dasatinib causes thrombocytopenia as a consequence of ineffective thrombopoiesis, promoting MK differentiation but also impairing MK migration and proplatelet formation.
机译：达沙替尼是Bcr-Abl，cKIT和Src家族激酶的一种新型，有效的，ATP竞争性抑制剂，在具有伊马替尼耐药的慢性粒细胞性白血病患者中显示出疗效。达沙替尼治疗与轻度血小板减少症和出血风险增加有关，但其对巨核细胞生成和血小板产生的生物学作用尚不清楚。在这项研究中，我们表明达沙替尼在不改变血小板半衰期的情况下在小鼠中引起轻度血小板减少症，表明它抑制了血小板的形成。相反，在达沙替尼的存在下，达沙替尼治疗的小鼠骨髓中的巨核细胞（MKs）数量增加，并且体外衍生自骨髓祖细胞的MK的倍体性增加。此外，在达沙替尼治疗的小鼠中观察到免疫诱导的血小板减少症后血小板恢复的显着延迟，即使相对于所有时间点，骨髓中MK的数量增加了。有趣的是，达沙替尼废除了MKs向基质细胞衍生因子1alpha（SDF1alpha）的梯度迁移和体外前血小板的形成。我们建议达沙替尼由于无效的血小板生成而导致血小板减少，促进MK分化，但也损害MK迁移和血小板形成。

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