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

Aged Aging / genetics Animals Apoptosis / genetics Cell Cycle / genetics Cell Proliferation / genetics Cells, Cultured Clonal Hematopoiesis / genetics DNA Damage / drug effects Gene Knock-In Techniques Hematopoiesis / genetics Hematopoietic Stem Cell Transplantation Hematopoietic Stem Cells / drug effects Humans Membrane Potential, Mitochondrial / drug effects Mice Mice, Transgenic Mutation Proto-Oncogene Proteins c-akt / metabolism RNA-Seq Reactive Oxygen Species / pharmacology Repressor Proteins / genetics Signal Transduction / drug effects Sirolimus / pharmacology TOR Serine-Threonine Kinases / metabolism Tumor Suppressor Proteins / metabolism Ubiquitin Thiolesterase / metabolism Ubiquitination / drug effects

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
23 03 2021

Historique:

received: 05 12 2019

accepted: 23 02 2021

entrez: 24 3 2021

pubmed: 25 3 2021

medline: 15 4 2021

Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-021-22053-y PMID: 33758188 PMC: PMC7988019

pubmed: 33758188

doi: 10.1038/s41467-021-22053-y

pii: 10.1038/s41467-021-22053-y

pmc: PMC7988019

doi:

Substances chimiques

Asxl1 protein, mouse 0

BAP1 protein, mouse 0

Reactive Oxygen Species 0

Repressor Proteins 0

Tumor Suppressor Proteins 0

Proto-Oncogene Proteins c-akt EC 2.7.11.1

TOR Serine-Threonine Kinases EC 2.7.11.1

Ubiquitin Thiolesterase EC 3.4.19.12

Sirolimus W36ZG6FT64

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1826

Subventions

Organisme : NCI NIH HHS

ID : P30 CA008748

Pays : United States

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