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Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging

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Jakobsen, Niels Asger, Turkalj, Sven, Zeng, Andy G.X., Stoilova, Bilyana, Metzner, Marlen, Rahmig, Susann, Nagree, Murtaza S., Shah, Sayyam +22 more·2024·Cell Stem Cell
DOI 10.1016/j.stem.2024.05.010PMC PMC11512683
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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.

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  • MYC targets were upregulated.

    “Interestingly, MYC targets were also upregulated ( Fig. 2k, Supplementary Table 6 ), thus corroborating a previous report demonstrating that IFNa upregulates MYC protein, which was thus postulated to regulate the cell cycle entry of HSCs in mice 52 .”

    From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [52]

    The Results sections on TET2-mutant progenitors and inflammatory responses report changes in other gene signatures, but do not identify upregulated MYC targets. Searches for MYC and for IFN-α-induced MYC protein in mouse HSCs found no passage addressing either point. The cited paper therefore does not verify the MYC claim in our copy. (LLM, conf=0.73)

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  • IFNa upregulates MYC protein, which was postulated to regulate the cell cycle entry of HSCs in mice.

    “Interestingly, MYC targets were also upregulated ( Fig. 2k, Supplementary Table 6 ), thus corroborating a previous report demonstrating that IFNa upregulates MYC protein, which was thus postulated to regulate the cell cycle entry of HSCs in mice 52 .”

    From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [52]

    The Results section on inflammatory transcriptional programs reports IFN-α response signatures in human HSC/MPPs, but does not say that IFN-α increases MYC protein or that MYC regulates cell-cycle entry in mouse HSCs. Searches for MYC and for the proposed IFN-α–MYC mechanism found no passage addressing that claim; page numbers were not available in our copy. (LLM, conf=0.75)

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Cited by

Sorted by citations

Authors
Jakobsen, N. A., Turkalj, S., Zeng, A. G. X., Stoilova, B., Metzner, M., Rahmig, S., Nagree, M. S., Shah, S., Moore, R., Usukhbayar, B., Angulo Salazar, M., Gafencu, G.-A., Kennedy, A., Newman, S., Kendrick, B. J. L., Taylor, A. H., Afinowi-Luitz, R., Gundle, R., Watkins, B., Wheway, K., Beazley, D., Murison, A., Aguilar-Navarro, A. G., Flores-Figueroa, E., Dakin, S. G., Carr, A. J., Nerlov, C., Dick, J. E., Xie, S. Z., & Vyas, P.
Affiliations
  • University of Oxford (GB)
  • University Health Network (CA)
  • Wellcome/MRC Cambridge Stem Cell Institute (GB)
  • Nuffield Orthopaedic Centre (GB)
  • Mexican Social Security Institute (MX)
Corresponding author
Vyas, Paresh
ORCID
Venue
Cell Stem Cell
Publisher
Elsevier BV
Published
2024-08
Volume
31
Issue
8
Pages
1127-1144.e17
ISSN
  • 1875-9777 (ISSN-L)
  • 1934-5909
DOI
10.1016/j.stem.2024.05.010
PMC
PMC11512683
OpenAlex
W4399970144
Cited by
130
References
24
Citations by year
2026: 66 · 2025: 51 · 2024: 13
FWCI
40.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell stem cell (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
Funders
  • Radcliffe Department of Medicine, University of Oxford
  • Blood Cancer UK (13008)
  • Government of Ontario
  • Manchester Biomedical Research Centre
  • Pfizer
  • Terry Fox Foundation
  • Clarendon Fund
  • National Research Council Canada
  • Princess Margaret Cancer Foundation
  • Canadian Institutes of Health Research (RN380110-409786)
  • Canada Research Chairs
  • University of Toronto
  • International Development Research Centre
  • Ministry of Health, Ontario
  • Ontario Institute for Cancer Research
  • Canadian Cancer Society Research Institute (703212)
  • University of Oxford
  • NIHR
  • Canada First Research Excellence Fund
  • Canadian Cancer Society
  • MRC (MC_UU_00029/8, MR/R002258/1)
  • Versus Arthritis
  • NIHR Oxford Biomedical Research Centre
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
Keywords
clonal hematopoiesis, hematopoietic stem cells, DNMT3A mutation, TET2 mutation, clonal expansion, inflammation, aging, myeloid maturation, non-cell-autonomous effects, single-cell multi-omics
MeSH terms
Clonal Hematopoiesis, DNA Methyltransferase 3A, Aging, DNA (Cytosine-5-)-Methyltransferases, DNA-Binding Proteins, Hematopoiesis, Hematopoietic Stem Cells, Humans, Inflammation, Mutation, Proto-Oncogene Proteins, Dioxygenases

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