Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway.

Somatic 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.
Mesh Terms:
Aged, Aging, Animals, Apoptosis, Cell Cycle, Cell Proliferation, Cells, Cultured, Clonal Hematopoiesis, DNA Damage, Gene Knock-In Techniques, Hematopoiesis, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Humans, Membrane Potential, Mitochondrial, Mice, Mice, Transgenic, Mutation, Proto-Oncogene Proteins c-akt, RNA-Seq, Reactive Oxygen Species, Repressor Proteins, Signal Transduction, Sirolimus, TOR Serine-Threonine Kinases, Tumor Suppressor Proteins, Ubiquitin Thiolesterase, Ubiquitination
Nat Commun
Date: Dec. 23, 2020
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