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Additional sex combs like 1 (ASXL1) is frequently mutated in myeloid malignancies, such as MDS (myelodysplastic syndromes) as well as clonal hematopoiesis of indeterminate potential (CHIP), a disorder characterized by clonal somatic mutations only in hematopoietic cells absent other criteria for hematologic malignancies [1]. CHIP is associated with an increased risk of coronary heart disease and atherosclerosis [2], which has attracted even more attention to the ASXL1 gene. Mutations in ASXL1 most commonly occur as frameshift and nonsense mutations in the last exon before the C-terminal plant homeofinger domain, suggesting that the mutant mRNA escapes from nonsense-mediated decay and that most ASXL1 mutations generate a stable truncated protein [3, 4]. Following the finding that truncated mutant forms of ASXL1 are detectable using mTRAQ-based mass spectrometric analysis [4], a growing number of mouse models with mutant expression have been developed. Recently, we generated conditional Asxl1 mutant (Asxl1MT) knock-in mice which mimic the human E635RfsX15 mutant and found that physiological expression of Asxl1-MT in vivo results in modest MDS-like disease, characterized by myeloid skewing, age-dependent anemia, thrombocytosis, and morphological dysplasia [5]. Although expression of Asxl1-MT reduced the number of hematopoietic stem cells (HSCs) and stemness similarly to other MDS mice models, it maintained HSC survival in competitive transplantation assays. Moreover, it increased susceptibility to leukemic transformation caused by co-occurring RUNX1 mutation or viral insertional mutagenesis, suggesting that these knock-in mice represent a novel model for CHIP [5]. Asx, the Drosophila melanogaster homologue of mammalian ASXL1-3, is required both to maintain repression and to activate expression of Hox genes, and ASXL genes are thought to mediate the balance between polycomb and trithorax functions [6], despite its lack of enzymatic activity. However, the role of the physiological expression of Asxl1-MT in histone modifications is not well understood. On ChIP-seq analysis, the Asxl1MT knock-in mice exhibited substantial reductions in H3K4me3 and H2AK119Ub, but not in H3K27me3 [5]. Although ASXL1 interacts with PRC2 (polycomb repressive complex 2) and that loss of ASXL1 or ectopic expression of its Asxl1-MT decrease global H3K27me3 [3, 7], H3K27me3 was downregulated only at specific loci, such as posterior Hoxa genes, highlighting the significance of our faithfully representative model. In line with these findings, the intensity of Asxl1 wild type (WT) binding was well correlated with H3K4me3 and H2AK119Ub abundance, but not that of H3K27me3, suggesting that WT protein can support H3K4 methylation and H2AK119 ubiquitination, not H3K27 methylation. Considering that nearly all Asxl1-MT binding sites were shared with WT binding sites (93.8%), it seems that ASXL1-MT inhibits or reverses the function of WT at the same loci in terms of H3K4 and H2AK119 modification (Figure 1). In fact, the intensity of Asxl1-MT binding tends to be correlated with the reduction of H3K4me3, especially in genes associated with erythroid differentiation, which may explain the observed age-dependent anemia, a characteristic symptom of MDS. To what extent can we explain the mechanism for the aberrant histone modification caused by Asxl1MT? With respect to loss of H2AK119Ub, Asada et al. and Balasubramani et al. demonstrated that ASXL1-MT cooperates with BAP1 to remove H2AK119 ubiquitination [8, 9] in a gain-of-function manner. Given that WT, not MT, can bind Bmi1 [10], a component of PRC1 (polycomb repressive complex 1), and that both WT and MT interact with BAP1 [8], the C-terminus of Asxl1 may be important Editorial

ASXL1 as a critical regulator of epigenetic marks and therapeutic potential of mutated cells