BMP2K dysregulation promotes abnormal megakaryopoiesis in acute megakaryoblastic leukemia

Abstract

Background: 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. Results: 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. Conclusions: 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.

Splicing variation of BMP2K balances endocytosis, COPII trafficking and autophagy in erythroid cells

“…A growing body of evidence suggests that AAK1 and BMP2K serine-threonine kinases might be of high importance for human physiology, with AAK1 implicated in functioning of the central nervous system (Kostich et al, 2016;Ultanir et al, 2012) and BMP2K involved in leukemogenesis (Hirabayashi et al, 2017;Pandzic et al, 2016;Wang et al, 2020). Although AAK1 is an established regulator of CME (Agajanian et al, 2019;Loi et al, 2016;Ricotta et al, 2002;Sorensen & Conner, 2008), the cellular functions of BMP2K are largely unknown.…”

Small peptide targeting ANP32A as a novel strategy for acute myeloid leukemia therapy

“…Western blotting was performed following a standard protocol [15] . Antibodies used in this study were listed in the Supplementary information.…”

Heterogeneous genomic architecture of skeletal armour traits in sticklebacks

“…LG4 (Fgf4, Fgf16, Fgf20, Jovelin et al 2007), the bone morphogenetic protein genes on LG17 (Bmp7, Shawi et al 2008;Bmp11, Indjeian et al 2016), and potentially the BMP-2-inducible protein kinase on LG13 (Bmp2k, Li and Cao 2006;Wang et al 2020). For the plate size variation, the fgf23 on LG19 and the Bmp7 and Bmp11 on LG17 were identified as candidate genes.…”