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

Abstract

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