Modeling ASXL1 mutation revealed impaired hematopoiesis caused by derepression of p16Ink4a through aberrant PRC1-mediated histone modification.

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. Asxl1^G643fs heterozygous (Asxl1^G643fs/+) 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 Asxl1^G643fs/+ 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 Asxl1^G643fs/+ 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 Asxl1^G643fs/+ 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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