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Published on: February 21, 2018
BMP2K dysregulation promotes abnormal megakaryopoiesis in acute megakaryoblastic leukemia
Manman Wang1, Tan Zhang1, Xuechun Zhang1
11College of Life Sciences, Wuhan University, No. 299 Bayi Road, Wuhan, Hubei 430072 People's Republic of China.
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.
Insights
Bone morphology protein 2-inducible kinase (BMP2K) suppresses megakaryocyte polyploidization and differentiation. BMP2K may be a therapeutic target for acute megakaryoblastic leukemia (AMKL) treatment.
Area of Science:
- Hematology
- Molecular Biology
- Cancer Research
Background:
- Forced polyploidization is a key strategy for treating acute megakaryoblastic leukemia (AMKL).
- Bone morphology protein 2-inducible kinase (BMP2K) is a potential target for polyploidy-inducing drugs, but its role in megakaryopoiesis and AMKL is unclear.
Purpose of the Study:
- To investigate BMP2K's function in megakaryocyte polyploidization and differentiation.
- To explore BMP2K's potential as a therapeutic target for AMKL.
Main Methods:
- Analyzed BMP2K expression in human megakaryopoiesis and AMKL cells.
- Investigated BMP2K's functional impact on megakaryocytic differentiation using cell models and primary mouse cells.
- Examined BMP2K's interaction with CDK2 and its effect on cell cycle regulation.
Main Results:
- BMP2K was upregulated in normal megakaryopoiesis but downregulated in differentiating AMKL cells.
- BMP2K suppressed megakaryocytic differentiation and conferred chemotherapy resistance in AMKL cells.
- BMP2K interacts with CDK2, regulates cell cycle progression (reducing G2/M, increasing G1), and antagonizes polyploidization.
Conclusions:
- BMP2K negatively regulates megakaryocyte polyploidization and differentiation by promoting mitosis via CDK2 interaction.
- BMP2K represents a potential therapeutic target for enhancing AMKL treatment strategies.
