Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway
Copyright policy )Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway
AbstractSomatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). HSCs expressing ASXL1-MT display competitive disadvantage after transplantation. Nevertheless, in genetic mosaic mouse model, they acquire clonal advantage during aging, recapitulating CH in humans. Mechanistically, ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT. Overactive Akt/mTOR signaling induced by ASXL1-MT results in aberrant proliferation and dysfunction of HSCs associated with age-related accumulation of DNA damage. Treatment with an mTOR inhibitor rapamycin ameliorates aberrant expansion of the HSC compartment as well as dysregulated hematopoiesis in aged ASXL1-MT KI mice. Our findings suggest that ASXL1-MT provokes dysfunction of HSCs, whereas it confers clonal advantage on HSCs over time, leading to the development of CH.
- University of Tokyo Japan
- Foundation for Biomedical Research United States
- Institute of Science Tokyo Japan
- Memorial Sloan Kettering Cancer Center United States
- Tokyo Women's Medical University Japan
Aging, Science, Apoptosis, Mice, Transgenic, Article, Mice, Animals, Humans, Gene Knock-In Techniques, RNA-Seq, Cells, Cultured, Aged, Cell Proliferation, Membrane Potential, Mitochondrial, Q, Cell Cycle, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Hematopoiesis, Mutation, Clonal Hematopoiesis, Proto-Oncogene Proteins c-akt, DNA Damage
Aging, Science, Apoptosis, Mice, Transgenic, Article, Mice, Animals, Humans, Gene Knock-In Techniques, RNA-Seq, Cells, Cultured, Aged, Cell Proliferation, Membrane Potential, Mitochondrial, Q, Cell Cycle, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Hematopoiesis, Mutation, Clonal Hematopoiesis, Proto-Oncogene Proteins c-akt, DNA Damage
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