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

Peng Zhang, Zizhen Chen, Rong Li, Ying Guo, Hui Shi, Jie Bai, Hui Yang, Mengyao Sheng, Zhaomin Li, Zhuo Li, Jianping Li, Shi Chen, Weiping Yuan, Tao Cheng, Mingjiang Xu, Yuan Zhou, Feng Chun Yang

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number4
JournalCell Discovery
Volume4
Issue number1
DOIs
StatePublished - Dec 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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  • Cite this

    Zhang, P., Chen, Z., Li, R., Guo, Y., Shi, H., Bai, J., Yang, H., Sheng, M., Li, Z., Li, Z., Li, J., Chen, S., Yuan, W., Cheng, T., Xu, M., Zhou, Y., & Yang, F. C. (2018). Loss of ASXL1 in the bone marrow niche dysregulates hematopoietic stem and progenitor cell fates. Cell Discovery, 4(1), [4]. https://doi.org/10.1038/s41421-017-0004-z