SRCAP mutations drive clonal hematopoiesis through epigenetic and DNA repair dysregulation.

Chen CW, Zhang L, Dutta R, Niroula A, Miller PG, Gibson CJ, Bick AG, Reyes JM, Lee YT, Tovy A, Gu T, Waldvogel S, Chen YH, Venters BJ, Estève PO, Pradhan S, Keogh MC, Natarajan P, Takahashi K, Sperling AS, Goodell MA

Cell Stem Cell 30 (11) 1503-1519.e8 [2023-11-02; online 2023-10-19]

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.

Abhishek Niroula

DDLS Fellow

PubMed 37863054

DOI 10.1016/j.stem.2023.09.011

Crossref 10.1016/j.stem.2023.09.011

pii: S1934-5909(23)00358-2

Publications 9.5.0