Publication Date
11-2-2023
Journal
Cell Stem Cell
DOI
10.1016/j.stem.2023.09.011
PMID
37863054
PMCID
PMC10841682
PubMedCentral® Posted Date
11-2-2024
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Animals, Humans, Mice, Adenosine Triphosphatases, Clonal Hematopoiesis, DNA Repair, Epigenesis, Genetic, Hematopoiesis, Mutation, clonal hematopoiesis, lymphoid, SRCAP, hematopoietic stem cells, chromatin remodeling, H2A.Z, DNA damage
Abstract
Somatic mutations accumulate in all cells with age and can confer a selective advantage, leading to clonal expansion over time. In hematopoietic cells, mutations in a subset of genes regulating DNA repair or epigenetics frequently lead to clonal hematopoiesis (CH). Here, we describe the context and mechanisms that lead to enrichment of hematopoietic stem cells (HSCs) with mutations in SRCAP, which encodes a chromatin remodeler that also influences DNA repair. We show that SRCAP mutations confer a selective advantage in human cells and in mice upon treatment with the anthracycline-class chemotherapeutic doxorubicin and bone marrow transplantation. Furthermore, Srcap mutations lead to a lymphoid-biased expansion, driven by loss of SRCAP-regulated H2A.Z deposition and increased DNA repair. Altogether, we demonstrate that SRCAP operates at the intersection of multiple pathways in stem and progenitor cells, offering a new perspective on the functional impact of genetic variants that promote stem cell competition in the hematopoietic system.
Graphical Abstract
Included in
Biological Phenomena, Cell Phenomena, and Immunity Commons, Life Sciences Commons, Medical Cell Biology Commons, Medical Microbiology Commons, Medical Molecular Biology Commons, Medical Specialties Commons
Comments
This article has been corrected. See Cell Stem Cell. 2024 Feb 1;31(2):275.
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