Abstract
Acute megakaryocytic leukemia (AMKL) is a rare neoplasm caused by abnormal megakaryoblasts. Megakaryoblasts keep dividing and avoid undergoing polyploidization to escape maturation. Small-molecule probes inducing polyploidization of megakaryocytic leukemia cells accelerate the differentiation of megakaryocytes. This study aims to determine that Rho kinase (ROCK) inhibition on megakaryoblasts enhances polyploidization and the inhibition of ROCK1 by fasudil benefits AMKL mice. The study investigated fasudil on the megakaryoblast cells in vitro and in vivo. With the differentiation and apoptosis induction, fasudil was used to treat 6133/MPLW515L mice, and the differentiation level was evaluated. Fasudil could reduce proliferation and promote the polyploidization of megakaryoblasts. Meanwhile, fasudil reduced the disease burden of 6133/MPLW515L AMKL mice at a dose that is safe for healthy mice. Combination therapy of ROCK1 inhibitor fasudil and reported clinical AURKA inhibitor MLN8237 achieved a better antileukemia effect in vivo, which alleviated hepatosplenomegaly and promoted the differentiation of megakaryoblast cells. ROCK1 inhibitor fasudil is a good proliferation inhibitor and polyploidization inducer of megakaryoblast cells and might be a novel rationale for clinical AMKL treatment.
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Abbreviations
- AMKL:
-
Acute megakaryocytic leukemia
- AML:
-
Acute myeloid leukemia
- ROCK:
-
Rho kinase
- CBC:
-
Complete blood counts
- AURKA:
-
Aurora kinase A
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Funding
This work is supported by the Natural Science Foundation of Beijing Municipality (2202021) and the National Natural Science Foundation of China (22072005, 21773015).
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All authors contributed to the study’s conception and design. Material preparation, data collection, and analysis were performed by He Binghong, Wang Chen, and Niu Jiajia. The first draft of the manuscript was written by He Binghong, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. The authors confirm that all data were generated in-house and that no paper mill was used.
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All animal studies were performed following the standards specified in the Animal Experimental Guidelines of the Chinese Medical Ethics Committee. The Laboratory Animal Ethics Committee of the College of Life Sciences of Beijing Normal University (2021–0074) approved all experimental protocols.
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He, B., Wang, C., Niu, J. et al. Fasudil promotes polyploidization of megakaryoblasts in an acute megakaryocyte leukemia model. Naunyn-Schmiedeberg's Arch Pharmacol 396, 3101–3110 (2023). https://doi.org/10.1007/s00210-023-02513-6
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DOI: https://doi.org/10.1007/s00210-023-02513-6