biostudies-literatureChen CWNIDCR NIH HHSNIA NIH HHSNational Heart, Lung, and Blood InstituteNHLBI NIH HHSKnut och Alice Wallenbergs StiftelseNIHCancer Prevention and Research Institute of TexasNovartis Pharmaceuticals CorporationNIDDK NIH HHSFondation LeducqU.S. Department of DefenseNHGRI NIH HHSNCI NIH HHSEdward P. Evans FoundationNIGMS NIH HHS1503-1519.e8https://www.ebi.ac.uk/biostudies/studies/S-EPMC10841682biostudies-literatureUnknown30(11)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. AlCell stem cellSRCAP mutations drive clonal hematopoiesis through epigenetic and DNA repair dysregulation.PMC10841682R01 HL148050CA212733R44 CA212733CA125123K08CA263183CA237291AG036695R01HL148565CA2108271P01CA265748RP180672R01 DK058192R44 GM136172DE029633KAW2017.0436HG011875GM136172R44 HG011875K08CA252174R56 DK092883P01 AG036695P30 CA125123K08 CA252174R01HL148050TNE - 18CVD04R01 DK092883R01 HL148565DK092883K08 CA263183R43 CA212733R44 DE029633R01 CA237291R01 CA183252P01 CA265748Gu TLee YTWaldvogel SVenters BJEsteve PODutta RSperling ASZhang LMiller PGGibson CJPradhan SKeogh MCTovy AGoodell MAChen YHNiroula ABick AGReyes JMChen CWTakahashi KNatarajan PfalseSRCAP mutations drive clonal hematopoiesis through epigenetic and DNA repair dysregulation.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. Al2023-01-01T00:00:00Z2023 Nov2026-06-02T04:08:52.838Z2025-04-06T00:58:58.728ZS-EPMC108416823786305410.1016/j.stem.2023.09.011