Abstract
ASXL2 is frequently mutated in acute myeloid leukaemia patients with t(8;21). However, the roles of ASXL2 in normal haematopoiesis and the pathogenesis of myeloid malignancies remain unknown. Here we show that deletion of Asxl2 in mice leads to the development of myelodysplastic syndrome (MDS)-like disease. Asxl2−/− mice have an increased bone marrow (BM) long-term haematopoietic stem cells (HSCs) and granulocyte–macrophage progenitors compared with wild-type controls. Recipients transplanted with Asxl2−/− and Asxl2+/− BM cells have shortened lifespan due to the development of MDS-like disease or myeloid leukaemia. Paired daughter cell assays demonstrate that Asxl2 loss enhances the self-renewal of HSCs. Deletion of Asxl2 alters the expression of genes critical for HSC self-renewal, differentiation and apoptosis in Lin−cKit+ cells. The altered gene expression is associated with dysregulated H3K27ac and H3K4me1/2. Our study demonstrates that ASXL2 functions as a tumour suppressor to maintain normal HSC function.
Highlights
ASXL2 is frequently mutated in acute myeloid leukaemia patients with t(8;21)
Convergent analyses of RNA sequencing (RNA-seq) and chromatin immunoprecipitation (ChIP) assays followed by sequencing (ChIP-seq) data in bone marrow (BM) Lin À cKit þ (LK) cells identified a subset of differentially expressed genes (DEGs), enriched with critical genes for haematopoietic stem cells (HSCs) function and apoptosis, as well as myelopoiesis
We examined whether Asxl[2] loss affected cell survival of HSC/HPCs by flow cytometric analysis on BM cells following Annexin V and 7-amino-actinomycin D (7-AAD) staining
Summary
ASXL2 is frequently mutated in acute myeloid leukaemia patients with t(8;21). the roles of ASXL2 in normal haematopoiesis and the pathogenesis of myeloid malignancies remain unknown. Paired daughter cell assays demonstrate that Asxl[2] loss enhances the self-renewal of HSCs. Deletion of Asxl[2] alters the expression of genes critical for HSC self-renewal, differentiation and apoptosis in Lin À cKit þ cells. Epigenetic alterations are frequently associated with myeloid malignancies by establishing specific gene expression profiles[1]. Asxl[1] loss leads to the development of myeloid malignancies in mice, which is associated with dysregulation of H3K27me[3] (refs 6,7). Enhancers and other distal regulatory elements are critical for context-specific gene regulation Such elements are associated with characteristic chromatin marks, including H3K4me[1] and H3K27ac, which facilitate their identification. Our results demonstrate a critical role of ASXL2 in the maintenance of normal HSC functions
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