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Cited by 132Acute Myeloid Leukemia ResearchCancer Genomics and DiagnosticsHematopoietic Stem Cell Transplantation

Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects

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Robertson, Neil A., Latorre-Crespo, Eric, Terradas-Terradas, Maria, Lemos-Portela, Jorge, Purcell, Alison C., Livesey, Benjamin J., Hillary, Robert F., Murphy, Lee +11 more·2022·Nature Medicine
DOI 10.1038/s41591-022-01883-3PMC PMC9307482

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Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) increases rapidly in prevalence beyond age 60 and has been associated with increased risk for malignancy, heart disease and ischemic stroke. CHIP is driven by somatic mutations in hematopoietic stem and progenitor cells (HSPCs). Because mutations in HSPCs often drive leukemia, we hypothesized that HSPC fitness substantially contributes to transformation from CHIP to leukemia. HSPC fitness is defined as the proliferative advantage over cells carrying no or only neutral mutations. If mutations in different genes lead to distinct fitness advantages, this could enable patient stratification. We quantified the fitness effects of mutations over 12 years in older age using longitudinal sequencing and developed a filtering method that considers individual mutational context alongside mutation co-occurrence to quantify the growth potential of variants within individuals. We found that gene-specific fitness differences can outweigh inter-individual variation and, therefore, could form the basis for personalized clinical management.

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  • Gene-specific fitness is independent of when the mutation was acquired.

    “Corroborative studies using longitudinal data have shown that gene-specific fitness is independent of when the mutation was acquired [44].”

    From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [44]

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Authors
Robertson, N. A., Latorre-Crespo, E., Terradas-Terradas, M., Lemos-Portela, J., Purcell, A. C., Livesey, B. J., Hillary, R. F., Murphy, L., Fawkes, A., MacGillivray, L., Copland, M., Marioni, R. E., Marsh, J. A., Harris, S. E., Cox, S. R., Deary, I. J., Schumacher, L. J., Kirschner, K., & Chandra, T.
Affiliations
  • MRC Human Genetics Unit (GB)
  • Cancer Research UK Scotland Institute (GB)
  • Institute of Genetics and Cancer (GB)
  • University of Edinburgh (GB)
  • University of Glasgow (GB)
  • MRC Centre for Regenerative Medicine (GB)
Corresponding author
  • Schumacher, Linus J.
  • Kirschner, Kristina
  • Chandra, Tamir
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2022-07
Volume
28
Issue
7
Pages
1439-1446
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-022-01883-3
PMC
PMC9307482
OpenAlex
W4283821860
Cited by
132
References
11
Citations by year
2026: 27 · 2025: 35 · 2024: 36 · 2023: 22 · 2022: 10 · 2021: 2
FWCI
18.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
Funders
  • Univesity of Edinburgh Chancellors Fellowships
  • RCUK | Medical Research Council (MR/N013166/1, MC_UU_00009/2, MR/M01311/1, MR/K026992/1)
  • University of Edinburgh Chancellors Fellowship
  • Leukemia UK
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 of indeterminate potential, hematopoietic stem and progenitor cells, somatic mutations, clonal fitness, co-occurring mutations, patient stratification, personalized medicine, aging
MeSH terms
Clonal Hematopoiesis, Hematopoiesis, Hematopoietic Stem Cells, Humans, Leukemia, Middle Aged, Mutation

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