Forced 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. BMP2K 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. BMP2K 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.

中文翻译：

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BMP2K 失调促进急性巨核细胞白血病的异常巨核细胞生成。

强制多倍化是急性巨核细胞白血病 (AMKL) 治疗的有效策略，控制多倍化的因素是药物开发的潜在目标。尽管骨形态蛋白 2 诱导激酶 (BMP2K) 已被暗示为 fasudil（一种有效的多倍体诱导化合物）的潜在靶标，但 BMP2K 在巨核细胞生成和 AMKL 中的功能仍然未知。本研究旨在探讨 BMP2K 作为一种新型调节因子在巨核细胞多倍体化和分化中的作用及其在 AMKL 治疗中的意义。在人类巨核细胞和白血病细胞中观察到 BMP2K 上调，而在被迫经历终末分化的 AMKL 细胞中 BMP2K 下调。在功能上，BMP2K 抑制 MLN8237 诱导的 AMKL 细胞中的巨核细胞分化并抑制原代小鼠胎儿肝细胞中的巨核细胞分化。此外，BMP2K 过表达赋予 AMKL 细胞对多种化疗化合物的抗性。从机制上讲，细胞周期蛋白依赖性激酶 2 (CDK2) 与 BMP2K 相互作用并部分介导其功能。在瞬时 MLN8237 和诺考达唑激发细胞模型中，BMP2K 降低了 G2/M 期的细胞百分比，但增加了 G1 期，表明 BMP2K 通过调节巨核生成中的细胞周期来拮抗多倍化和促进有丝分裂的作用。BMP2K 通过与 CDK2 相互作用并促进巨核细胞生成中的有丝分裂来负调节多倍体化和巨核细胞分化。BMP2K 可作为改善 AMKL 治疗的潜在靶点。