1. Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging.
- Author
-
Jakobsen NA, Turkalj S, Zeng AGX, Stoilova B, Metzner M, Rahmig S, Nagree MS, Shah S, Moore R, Usukhbayar B, Angulo Salazar M, Gafencu GA, Kennedy A, Newman S, Kendrick BJL, Taylor AH, Afinowi-Luitz R, Gundle R, Watkins B, Wheway K, Beazley D, Murison A, Aguilar-Navarro AG, Flores-Figueroa E, Dakin SG, Carr AJ, Nerlov C, Dick JE, Xie SZ, and Vyas P
- Subjects
- Humans, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Hematopoiesis genetics, Inflammation genetics, Inflammation pathology, Aging genetics, Clonal Hematopoiesis genetics, Mutation genetics, DNA Methyltransferase 3A, Dioxygenases, Hematopoietic Stem Cells metabolism, DNA (Cytosine-5-)-Methyltransferases genetics, DNA (Cytosine-5-)-Methyltransferases metabolism
- Abstract
Clonal hematopoiesis (CH) arises when hematopoietic stem cells (HSCs) acquire mutations, most frequently in the DNMT3A and TET2 genes, 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 TET2 mutations 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., Competing Interests: Declaration of interests J.E.D. receives royalties from Trillium Therapeutics Inc./Pfizer and a commercial research grant from Celgene/BMS., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF