Abstract
In spite of distinct clinical importance, the molecular mechanisms how Additional sex combs-like 1 (ASXL1) mutation contributes to the pathogenesis of premalignant conditions are largely unknown. Here, with newly generated knock-in mice, we investigated the biological effects of the mutant. Asxl1G643fs heterozygous (Asxl1G643fs/+) mice developed phenotypes recapitulating human low-risk myelodysplastic syndromes (MDS), and some of them developed MDS/myeloproliferative neoplasm-like disease after long latency. H2AK119ub1 level around the promoter region of p16Ink4a was significantly decreased in Asxl1G643fs/+ hematopoietic stem cells (HSC), suggesting perturbation of Bmi1-driven H2AK119ub1 histone modification by mutated Asxl1. The mutant form of ASXL1 had no ability to interact with BMI1 as opposed to wild-type ASXL1 protein. Restoration of HSC pool and amelioration of increased apoptosis in hematopoietic stem and progenitor cells were obtained from Asxl1G643fs/+ mice heterozygous for p16Ink4a. These results indicated that loss of protein interaction between Asxl1 mutant and Bmi1 affected the activity of PRC1, and subsequent derepression of p16Ink4a by aberrant histone ubiquitination could induce cellular senescence, resulting in low-risk MDS-like phenotypes in Asxl1G643fs/+ mice. This model provides a useful platform to unveil the molecular basis for hematological disorders induced by ASXL1 mutation and to develop therapeutic strategies for these patients.
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Acknowledgements
We thank Dr. Sharpless for p16Ink4a null mice, Dr. Tokushige for the beautiful picture of skeletal preparations, and Ms. Yamamoto for expert technical assistance. This study was supported in part by the Japan Society for the Promotion of Science (JSPS) KAKENHI (No. 23112504, 26860721).
Author contributions
Conceptualization: MU, YM, and MK; methodology: MU, YM, TS, YK, SA, and MK; investigation: MU; resources: TS, YK, EH, and MK; writing—original draft: MU; writing—review and editing: all the authors; funding acquisition: TS, YK, and MK; supervision: YM and MK; project administration: MK.
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Uni, M., Masamoto, Y., Sato, T. et al. Modeling ASXL1 mutation revealed impaired hematopoiesis caused by derepression of p16Ink4a through aberrant PRC1-mediated histone modification. Leukemia 33, 191–204 (2019). https://doi.org/10.1038/s41375-018-0198-6
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DOI: https://doi.org/10.1038/s41375-018-0198-6
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