BMP2K dysregulation promotes abnormal megakaryopoiesis in acute megakaryoblastic leukemia
BMP2K dysregulation promotes abnormal megakaryopoiesis in acute megakaryoblastic leukemia
复制标题
BMP2K 失调促进急性巨核细胞白血病异常巨核细胞生成
DOI：
10.1186/s13578-020-00418-y
复制
发表时间：
2020-04-15
影响因子：
7.5
通讯作者：
Huang, Zan
中科院分区：
文献类型：
--
作者：
Wang, Manman;Zhang, Tan;Huang, Zan
强制多倍化是治疗急性巨核细胞白血病(AMKL)的有效策略，控制多倍化的因素是药物开发的潜在靶点。尽管骨形态蛋白2诱导蛋白(BMP2K)已被认为是一种有效的多倍体诱导化合物法舒地尔的潜在靶点，但BMP2K在巨核细胞生成和AMKL中的作用仍不清楚。本研究旨在探讨BMP2K作为一种新的调控因子在巨核细胞多倍化和分化中的作用及其在AMKL治疗中的意义。结果BMP2K在人巨核细胞和白血病细胞中表达上调，而在被迫进行终末分化的AMKL细胞中BMP2K表达下调。在功能上，BMP2K抑制MLN8237诱导的AMKL细胞的巨核细胞分化，并抑制原代小鼠胎肝细胞的巨核细胞分化。此外，BMP2K过表达使AMKL细胞对多种化疗药物产生耐药。在机制上，细胞周期蛋白依赖的蛋白2(CDK2)与BMP2K相互作用并部分介导其功能。在瞬时MLN8237和诺可达唑攻击细胞模型中，BMP2K使G2/M期细胞比例减少，而G1期细胞比例增加，提示BMP2K可能通过调节巨核细胞周期而拮抗多倍化，促进有丝分裂。结论BMP2K通过与CDK2相互作用，促进巨核细胞有丝分裂，对多倍化和巨核细胞分化具有负性调节作用。BMP2K可作为AMKL治疗改进的潜在靶点。
BackgroundForced polyploidization is an effective strategy for acute megakaryoblastic leukemia (AMKL) therapy and factors controlling polyploidization are potential targets for drug development. Although bone morphology protein 2-inducible kinase (BMP2K) has been implied to be a potential target for fasudil, a potent polyploidy-inducing compound, the function of BMP2K in megakaryopoiesis and AMKL remains unknown. This study aimed to investigate the role of BMP2K as a novel regulator in megakaryocyte polyploidization and differentiation and its implication in AMKL therapy.ResultsBMP2K upregulation was observed in human megakaryopoiesis and leukemia cells whereas BMP2K was downregulated in AMKL cells forced to undergo terminal differentiation. Functionally, BMP2K suppressed MLN8237-induced megakaryocytic differentiation in AMKL cells and dampened megakaryocyte differentiation in primary mouse fetal liver cells. Furthermore, BMP2K overexpression conferred resistance to multiple chemotherapy compounds in AMKL cells. Mechanistically, cyclin-dependent kinase 2 (CDK2) interacted with BMP2K and partially mediated its function. In transient MLN8237 and nocodazole challenge cell model, BMP2K reduced cell percentage of G2/M phase but increased G1 phase, suggesting a role of BMP2K antagonizing polyploidization and promoting mitosis by regulating cell cycle in megakaryopoiesis.ConclusionsBMP2K negatively regulates polyploidization and megakaryocyte differentiation by interacting CDK2 and promoting mitosis in megakaryopoiesis. BMP2K may serve as a potential target for improvement of AMKL therapy.