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Somatic or de novo mutations of  Additional sex combs-like 1  ( ASXL1 ) frequently occur in patients with myeloid malignancies or Bohring-Opitz syndrome, respectively. We have reported that global loss of  Asxl1  leads to the development of myeloid malignancies and impairs bone marrow stromal cell (BMSC) fates in mice. However, the impact of  Asxl1  deletion in the BM niche on hematopoiesis remains unclear. Here, we showed that BMSCs derived from chronic myelomonocytic leukemia patients had reduced expression of  ASXL1 , which impaired the maintaining cord blood CD34 +  cell colony-forming capacity with a myeloid differentiation bias. Furthermore,  Asxl1  deletion in the mouse BMSCs altered hematopoietic stem and progenitor cell (HSC/HPC) pool and a preferential myeloid lineage increment. Immunoprecipitation and ChIP-seq analyses demonstrated a novel interaction of ASXL1 with the core subunits of RNA polymerase II (RNAPII) complex. Convergent analyses of RNA-seq and ChIP-seq data revealed that loss of  Asxl1  deregulated RNAPII transcriptional function and altered the expression of genes critical for HSC/HPC maintenance, such as  Vcam1 . Altogether, our study provides a mechanistic insight into the function of ASXL1 in the niche to maintain normal hematopoiesis; and  ASXL1  alteration in, at least, a subset of the niche cells induces myeloid differentiation bias, thus, contributes the progression of myeloid malignancies.

Loss of ASXL1 in the bone marrow niche dysregulates hematopoietic stem and progenitor cell fates