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

Zhang et al. Cell Discovery 2018 4:4

Speaker: Irwin Puc (傅立宇)                                                 Time: 14:00-15:00, April. 11, 2018

Commentator: Dr. Michael Hughes (修臥龍)                          Place: Room 601

Abstract:

The additional Sex Combs-Like 1 (ASXL1) gene is essential in providing instructions for making a protein that is involved in a process known as chromatin remodeling. Chromatin is described as a complex of DNA and proteins that packages DNA into chromosomes. The structure of chromatin can be changed (remodeled) to alter how tightly DNA is packaged, when this happens DNA is tightly packed, gene activity (expression) is lower than when DNA is loosely packed. Other studies have demonstrated multifaceted functions of the ASXL1 protein, for example it may have an additional role in gene regulation by signaling to molecules to add a methyl group (a process called methylation) to an area near a gene called the promoter region, which controls gene activity. When a promoter region is methylated, gene activity is repressed, and when a promoter region is not methylated, the gene is active. The ASXL1 gene is located in the chromosomal region 20q11, ASXL1 mutations are often found in a wide range of myeloid malignancies and its alterations are associated with poor prognosis. Previous research has shown that global loss of Asxl1 leads to the development of myeloid malignancies, developmental defects, microcephaly and impairs bone marrow stromal cell (BMSC) fates in mice. In this paper the author demonstrates that BMSCs derived from chronic myelomonocytic leukemia patients had reduced expression of ASXL1, which in result impaired the maintenance cord blood CD34+ cell colony-forming capacity with a myeloid differentiation bias. To further evaluate the effect of ASXL1 loss, ASXL1 was deleted in mouse BMSCs and showed to alter hematopoietic stem and progenitor cell (HSC/HPC) pool and a preferential myeloid lineage. Unprecedented data of Immunoprecipitation and ChIP-seq analysis demonstrated a distinct interaction of ASXL1 with the core subunits of RNA polymerase II (RNAPII) complex. Convergent analyses of RNA-seq and ChIP-seq data showed that loss of Asxl1 deregulated RNAPII transcriptional function and altered the expression of genes that are crucial for HSC/HPC maintenance. Overall, this study provides a mechanistic insight in understanding the function of ASXL1 in the BM niche to maintain normal hematopoiesis; and ASXL1 alteration induces myeloid differentiation bias, thus, contributing the progression of myeloid malignancies.

References:

Carbuccia, N., Murati, A., Trouplin, V., Brecqueville, M., & Adélaïde, J. (2009). Mutations of ASXL1 gene in myeloproliferative neoplasms. Leukemia, 23. doi: doi:10.1038/leu.2009.141

Kitamura, T. (2018). http://www.bloodjournal.org/content/131/3/274?sso-checked=true. American Society of Hematology, 131, 274-275. doi: https://doi.org/10.1182/blood-2017-12-816595

U.S. National Library of Medicin. (December 2016).   Retrieved April 10, 2018, from https://ghr.nlm.nih.gov/gene/ASXL1#resources