1. Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging
- Author
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Jakobsen, Niels Asger, Turkalj, Sven, Zeng, Andy G.X., Stoilova, Bilyana, Metzner, Marlen, Rahmig, Susann, Nagree, Murtaza S., Shah, Sayyam, Moore, Rachel, Usukhbayar, Batchimeg, Angulo Salazar, Mirian, Gafencu, Grigore-Aristide, Kennedy, Alison, Newman, Simon, Kendrick, Benjamin J.L., Taylor, Adrian H., Afinowi-Luitz, Rasheed, Gundle, Roger, Watkins, Bridget, Wheway, Kim, Beazley, Debra, Murison, Alex, Aguilar-Navarro, Alicia G., Flores-Figueroa, Eugenia, Dakin, Stephanie G., Carr, Andrew J., Nerlov, Claus, Dick, John E., Xie, Stephanie Z., and Vyas, Paresh
- Abstract
Clonal hematopoiesis (CH) arises when hematopoietic stem cells (HSCs) acquire mutations, most frequently in the DNMT3Aand TET2genes, conferring a competitive advantage through mechanisms that remain unclear. To gain insight into how CH mutations enable gradual clonal expansion, we used single-cell multi-omics with high-fidelity genotyping on human CH bone marrow (BM) samples. Most of the selective advantage of mutant cells occurs within HSCs. DNMT3A- and TET2-mutant clones expand further in early progenitors, while TET2mutations accelerate myeloid maturation in a dose-dependent manner. Unexpectedly, both mutant and non-mutant HSCs from CH samples are enriched for inflammatory and aging transcriptomic signatures, compared with HSCs from non-CH samples, revealing a non-cell-autonomous effect. However, DNMT3A- and TET2-mutant HSCs have an attenuated inflammatory response relative to wild-type HSCs within the same sample. Our data support a model whereby CH clones are gradually selected because they are resistant to the deleterious impact of inflammation and aging.
- Published
- 2024
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