Abstract
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.
Highlights
Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH)
We confirmed that ASXL1-MT causes a competitive disadvantage of LT-hematopoietic stem cells (HSCs) after transplantation
long-term HSCs (LT-HSCs) expressing ASXL1-MT acquire a growth advantage and eventually occupy the HSC compartment during aging in genetic mosaic mouse model. This observation is clearly distinct from that of DNMT3A or TET2 mutations, which exhibits an increase in the long-term regenerative potential of HSCs
Summary
Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). 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). Most ASXL1 mutations detected in CH and hematological malignancies are frameshift or nonsense mutations in the last exon, generating a C-terminally truncated form of ASXL114,15,17–21 Such truncated ASXL1 proteins are expressed in leukemic cells and likely confer change-of-function[22]. In hematopoietic lineage-specific conditional knockin (KI) mice expressing a C-terminally truncated form of mutant ASXL1 (ASXL1-MT; 1900−1922del;E635RfsX15)[25], global reduction was observed in H3K4me[3] and H2AK119Ub. In particular, levels of H3K4me[3] at the loci of erythroid differentiation-related genes, such as Id3 and Sox[6], were markedly decreased, suggesting that ASXL1-MT impairs hematopoiesis through dysregulated epigenetic modifications. These molecular changes can cause CH with increased risk of leukemogenesis, which can be ameliorated by rapamycin treatment
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