Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cells, Leading to Bohring-Opitz-like Syndrome in Mice
Year: 2016
Type: article
Abstract: De novo ASXL1 mutations are found in patients with Bohring-Opitz syndrome, a disease with severe developmental defects and early childhood mortality. The underlying pathologic mechanisms remain largely unknown. Using Asxl1-targeted murine models, we found that Asxl1 global loss as well as conditional deletion in osteoblasts and their progenitors led to significant bone loss and a markedly decreased number of bone marrow stromal cells (BMSCs) compared with wild-type littermates. Asxl1(-/-) BMSCs displayed impaired self-renewal and skewed differentiation, away from osteoblasts and favoring adipocytes. RNA-sequencing analysis revealed altered expression of genes involved in cell proliferation, skeletal development, and morphogenesis. Furthermore, gene set enrichment analysis showed decreased expression of stem cell self-renewal gene signature, suggesting a role of Asxl1 in regulating the stemness of BMSCs. Importantly, re-introduction of Asxl1 normalized NANOG and OCT4 expression and restored the self-renewal capacity of Asxl1(-/-) BMSCs. Our study unveils a pivotal role of ASXL1 in the maintenance of BMSC functions and skeletal development.
Source: Stem Cell Reports
Institutions: University of Miami, Sylvester Comprehensive Cancer Center, Chinese Center For Disease Control and Prevention, Chinese Academy of Sciences, Beijing Institute of Genomics, National Institute for Occupational Health and Poison Control, Indiana University School of Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Institute of Hematology & Blood Diseases Hospital, State Key Laboratory of Experimental Hematology, Memorial Sloan Kettering Cancer Center
Language: English
Topic: Bone Metabolism and Diseases
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,190
Awards: Role of Asxl1 in normal hematopoiesis and pathogenesis of myeloid malignancies, No-nonsense approach to treat myeloid malignancies with ASXL1 nonsense mutations, Differential TGF-Beta Signaling in Bone Microenviroment: Impact on Tumor Growth, 苯通过影响DNA修复引起造血干祖细胞基因组突变的机制研究, Role of TET2 in normal hematopoiesis and pathogenesis of myeloid malignancies, G8094210831, Cancer Center Support Grant
OpenAlex ID: W2400327738