Abstract
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.
Highlights
Polyploidization and functional maturation are two accompanying and distinct processes of megakaryopoiesis [1]
bone morphology protein 2-inducible kinase (BMP2K) is involved with normal and malignant megakaryopoiesis Previous studies suggest that BMP2K may be a potential regulator of blood stem/progenitor cells [12] as well as acute megakaryoblastic leukemia (AMKL) [5]
The public database (Bloodspot, https://servers.binf.ku.dk/bloodspot/) showed upregulation of BMP2K in megakaryocyte lineage compared to hematopoietic stem cell (HSC) (Fig. 1a)
Summary
Polyploidization and functional maturation are two accompanying and distinct processes of megakaryopoiesis [1]. RhoA pathway is a critical regulator of cleavage furrow formation and ingression in mitosis. Deficiency in RhoA pathway activation that results in failure of cleavage furrow formation is essential for endomitosis [4]. MLN8237 (Alisertib), a selective inhibitor of aurora kinase A (AURKA), has been reported to induce polyploidization and the expression of mature megakaryocyte markers in AMKL and PMF blasts by promoting the transition from the proliferative cell cycle to an endomitosis [5, 6]. The exact mechanism determining whether megakaryocytes undergo mitosis or endomitosis remains unresolved, identification of pivotal polyploidy-inducing regulators may help address this issue and provide potential targets for AMKL therapy. 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
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