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The longitudinal dynamics and natural history of clonal haematopoiesis

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Fabre, Margarete A., de Almeida, José Guilherme, Fiorillo, Edoardo, Mitchell, Emily, Damaskou, Aristi, Rak, Justyna, Orrù, Valeria, Marongiu, Michele +13 more·2022·Nature
DOI 10.1038/s41586-022-04785-zPMC PMC9177423

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Abstract

Clonal expansions driven by somatic mutations become pervasive across human tissues with age, including in the haematopoietic system, where the phenomenon is termed clonal haematopoiesis 1–4 . The understanding of how and when clonal haematopoiesis develops, the factors that govern its behaviour, how it interacts with ageing and how these variables relate to malignant progression remains limited 5,6 . Here we track 697 clonal haematopoiesis clones from 385 individuals 55 years of age or older over a median of 13 years. We find that 92.4% of clones expanded at a stable exponential rate over the study period, with different mutations driving substantially different growth rates, ranging from 5% ( DNMT3A and TP53 ) to more than 50% per year ( SRSF2 P95H ). Growth rates of clones with the same mutation differed by approximately ±5% per year, proportionately affecting slow drivers more substantially. By combining our time-series data with phylogenetic analysis of 1,731 whole-genome sequences of haematopoietic colonies from 7 individuals from an older age group, we reveal distinct patterns of lifelong clonal behaviour. DNMT3A -mutant clones preferentially expanded early in life and displayed slower growth in old age, in the context of an increasingly competitive oligoclonal landscape. By contrast, splicing gene mutations drove expansion only later in life, whereas TET2 -mutant clones emerged across all ages. Finally, we show that mutations driving faster clonal growth carry a higher risk of malignant progression. Our findings characterize the lifelong natural history of clonal haematopoiesis and give fundamental insights into the interactions between somatic mutation, ageing and clonal selection.

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  • Loss-of-function heterozygous mutations in DNMT3A account for about 50% to 60% of mutations found in CHIP carriers.

    “Loss-of-function heterozygous mutations in epigenetic regulators DNMT3A (cytosine methyltransferase) and TET2 (methylcytosine dioxygenase) are the most frequently detected mutations in CHIP, accounting for about 50% to 60% and 10% to 30% of mutations found in CHIP carriers, respectively.1, 2, 3,7,8”

    From Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [8]

    The Mutational landscape section (page unavailable) says DNMT3A and TET2 were the most commonly mutated epigenetic regulator genes, and the Discussion (page unavailable) calls DNMT3A reportedly the most common clonal-haematopoiesis driver gene. Neither passage establishes that heterozygous loss-of-function DNMT3A mutations account for 50%–60% of mutations in CHIP carriers. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Loss-of-function heterozygous mutations in TET2 account for about 10% to 30% of mutations found in CHIP carriers.

    “Loss-of-function heterozygous mutations in epigenetic regulators DNMT3A (cytosine methyltransferase) and TET2 (methylcytosine dioxygenase) are the most frequently detected mutations in CHIP, accounting for about 50% to 60% and 10% to 30% of mutations found in CHIP carriers, respectively.1, 2, 3,7,8”

    From Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [8]

    The Mutational landscape of clonal haematopoiesis section says TET2 and DNMT3A mutations were the most common in the studied cohort. It does not give the claimed 10%–30% share for TET2 mutations in CHIP carriers or establish that those mutations were heterozygous loss-of-function mutations. The Determinants of clonal growth rate section discusses truncating and missense TET2 mutations but does not establish those qualifiers or the percentage. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • In CHIP, TET2 mutations show highest clonal expansion rates over time, with an estimated 10% annual growth rate compared with 5% for DNMT3A mutations.

    “In the context of CHIP, TET2 mutations show highest clonal expansion rates over time (with an estimated 10% annual growth rate compared with 5% of DNMT3A mutations7,8,10).”

    From Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [8]

    The ‘Determinants of clonal growth rate’ section (page not provided) reports average annual growth of about 10% for TET2-mutant clones versus 5% for DNMT3A-mutant clones. It does not support calling TET2 the highest: SRSF2-, PTPN11- and U2AF1-mutant clones grew faster, at 15–20% per year on average. (LLM, conf=0.91)

    Experimental — accuracy not yet measured

  • CH-associated variants of Dnmt3a and Tet2 affect the HSPC methylome and have been shown to alter functions of monocyte-derived tissue macrophages and promote cardiovascular pathologies.

    “CH-associated variants of the epigenetic writers and erasers Dnmt3a and Tet2, respectively, that affect the HSPC methylome have been shown to alter functions of monocyte-derived tissue M F and promote cardiovascular pathologies 31-34 .”

    From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [33]

    The Main section identifies DNMT3A and TET2 as clonal-haematopoiesis genes involved in epigenetic regulation. It does not establish that their variants change the HSPC methylome, alter monocyte-derived tissue macrophage function, or promote cardiovascular disease. The Discussion addresses clonal growth rather than those outcomes; a cardiovascular-disease title appears only in the References. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • DNMT3A mutant clones are relatively slow-growing at ~5% per year while SRSF2 mutant clones may grow as fast as 20% per year.

    “for example, DNMT3A mutant clones are relatively slow-growing at ~5% per year while SRSF2 mutants clones may grow as fast as 20% per year [21].”

    From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [21]

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Authors
Fabre, M. A., de Almeida, J. G., Fiorillo, E., Mitchell, E., Damaskou, A., Rak, J., Orrù, V., Marongiu, M., Chapman, M. S., Vijayabaskar, M. S., Baxter, J., Hardy, C., Abascal, F., Williams, N., Nangalia, J., Martincorena, I., Campbell, P. J., McKinney, E. F., Cucca, F., Gerstung, M., & Vassiliou, G. S.
Affiliations
  • Wellcome/MRC Cambridge Stem Cell Institute (GB)
  • Institute of Genetic and Biomedical Research (IT)
  • Wellcome Sanger Institute (GB)
  • University of Cambridge (GB)
  • University of Sassari (IT)
  • European Bioinformatics Institute (GB)
Corresponding author
  • Gerstung, Moritz
  • Vassiliou, George S.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2022-06-01
Volume
606
Issue
7913
Pages
335-342
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-022-04785-z
PMC
PMC9177423
OpenAlex
W4281780963
Cited by
374
References
12
Citations by year
2026: 62 · 2025: 94 · 2024: 87 · 2023: 88 · 2022: 40 · 2021: 2 · 2020: 1
FWCI
56.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • UnissResearch (Università degli Studi di Sassari) (submittedVersion)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo
  • Apollo (cc-by)
Funders
  • Leukemia and Lymphoma Society (RTF6006-19)
  • Wellcome Trust (104064/Z/14/Z, WT 098051, 098051)
  • Cancer Research UK (23015, 23917, 21777, WT098051)
  • National Institute for Health and Care Research
  • Department of Health and Social Care
  • Kay Kendall Leukaemia Fund
  • European Commission (633964)
  • Blood Cancer UK
  • Rising Tide Foundation for Clinical Cancer Research
  • Rising Tide Foundation
  • National Institutes of Health (N01-AG-1-2109, HHSN271201100005C, H2020)
  • Horizon 2020 Framework Programme (EC H2020)
  • Medical Research Council (MC_PC_17230)
  • NIHR Cambridge Biomedical Research Centre
  • National Institute on Aging (N01-AG-12109, N01-AG-1-2109 and HHSN271201100005C, HHSN271201100005C)
  • National Institute on Drug Abuse (HHSN271201100005C)
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
Keywords
clonal hematopoiesis, somatic mutations, DNMT3A, TP53, TET2, aging, malignant progression, clonal selection, phylogenetic analysis, hematopoietic stem cells, long-term tracking
MeSH terms
Clonal Hematopoiesis, Aged, Aging, Clone Cells, Humans, Longitudinal Studies, Middle Aged, Mutation, Phylogeny, Genome, Human

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