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

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. Asxl1 heterozygous (Asxl1) 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 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 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 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.

Impact of Mesenchymal Stem Cell Senescence on Inflammaging

“…In fact, Asxl1 mutant mice showed spontaneous development of peripheral leukopenia and dysplastic myeloid cells in BM, and ex vivo analyses revealed various pathogenic features of MDS, including aberrant myeloid differentiation with a significant increase of granulocytic and monocytic cell fraction, and considerable growth arrest of HSC pool mediated by apoptosis and cell-cycle arrest. In addition to hematopoiesis, the mice showed impaired development in body size and weight (95). It is well defined that deletion of the epigenetic modulator gene ASXL1 in myeloid cells results in upregulated osteoclastogenesis in association with reduction of H3K27me3 through inhibition, suggesting diminished bone mass and subsequently impaired BM niche function (94).…”

Role of ASXL1 mutation in impaired hematopoiesis and cellular senescence

“…So we generated Asxl1 mutant locus knock-in (KI) mice, and investigated the biological effects of the mutant. Intriguingly, heterozygous mutant mice developed phenotypes recapitulating human low-risk MDS, and the impared hematopoiesis shown in the KI mice was explained by cellular senescence induced by derepression of p16Ink4a due to perturbation of Bmi1-driven H2AK119ub1 histone modification [6]. On the other hand, the impact of tri-methylation of H3K27 and resultant upregulation of posterior Hoxa genes were limited compared with previous ASXL1 mutant or knock-out mice models.…”

RASmutations drive proliferative chronic myelomonocytic leukemia via activation of a novel KMT2A-PLK1 axis

“…By using ChIP-seq in CMML samples, we demonstrate that H3K27me3 occupancy and recruitment at PLK1 and WEE1 promoters is not significantly different in RAS pathway mutated pCMML in comparison to RAS pathway wildtype dCMML, regardless of the ASXL1 mutational status (sequence specific analysis restricted to PLK1 and WEE1). Asxl1 G643fs het knock in mice develop low risk MDS like features with very few animals developing MDS/MPN overlap syndromes like CMML and without AML transformation (Uni et al, 2019). Similarly, by carrying out DIP-seq, we demonstrate that there were no differences in 5-mc or 5-hmc levels at the promotors of PLK1 and WEE1 in RAS pathway mutant pCMML and RAS pathway wild-type dCMML patient samples, regardless of their TET2 mutational status (sequence specific analysis restricted to PLK1 and WEE1).…”