Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis
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Clonal hemopoiesis driven by leukemia-associated gene mutations can occur without evidence of a blood disorder. To investigate this phenomenon, we interrogated 15 mutation hot spots in blood DNA from 4,219 individuals using ultra-deep sequencing. Using only the hot spots studied, we identified clonal hemopoiesis in 0.8% of individuals under 60, rising to 19.5% of those ≥90 years, thus predicting that clonal hemopoiesis is much more prevalent than previously realized. DNMT3A-R882 mutations were most common and, although their prevalence increased with age, were found in individuals as young as 25 years. By contrast, mutations affecting spliceosome genes SF3B1 and SRSF2, closely associated with the myelodysplastic syndromes, were identified only in those aged >70 years, with several individuals harboring more than one such mutation. This indicates that spliceosome gene mutations drive clonal expansion under selection pressures particular to the aging hemopoietic system and explains the high incidence of clonal disorders associated with these mutations in advanced old age.
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Subsequent studies in healthy persons using more sensitive approaches have found the prevalence of clonal hematopoiesis to be much higher than initial whole-exome sequencing studies.
“Subsequent studies in healthy persons using more sensitive approaches have found the prevalence of clonal hematopoiesis to be much higher, although the biological significance of the smaller clones is unknown 31–33.”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [31]
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- Authors
- McKerrell, T., Park, N., Moreno, T., Grove, C. S., Ponstingl, H., Stephens, J., Crawley, C., Craig, J., Scott, M. A., Hodkinson, C., Baxter, J., Rad, R., Forsyth, D. R., Quail, M. A., Zeggini, E., Ouwehand, W., Varela, I., & Vassiliou, G. S.
- Affiliations
- Wellcome Sanger Institute (GB)
- NHS Blood and Transplant (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- University of Cambridge (GB)
- German Cancer Research Center (DE)
- Universidad de Cantabria (ES)
- Corresponding author
- Vassiliou, George S.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2015-03
- Volume
- 10
- Issue
- 8
- Pages
- 1239-1245
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4542313
- OpenAlex
- W2073440691
- Cited by
- 534
- References
- 39
- Citations by year
- 2026: 26 · 2025: 36 · 2024: 33 · 2023: 48 · 2022: 43 · 2021: 45 · 2020: 52 · 2019: 49 · 2018: 65 · 2017: 64 · 2016: 43 · 2015: 29 · 2014: 1
- FWCI
- 52.68
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCrea (University of Cantabria) (publishedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by-nc-nd)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Apollo (cc-by)
- Funders
- Foundation for the National Institutes of Health
- Celgene
- University of Essex
- Wellcome Trust (WT061858, 061858, 095663, WT 098051, 100678/Z/12/Z, WT095663MA, 076113, 076113/C/04/Z)
- Understanding Society
- National Institute for Health and Care Research (NF-SI-0510-10214, RP-PG-0310-1002, NF-SI-0513-10151)
- British Heart Foundation (RG/09/012/28096)
- Leukaemia and Lymphoma Research
- Ministerio de Economía y Competitividad
- Economic and Social Research Council (ES/H029745/1)
- Research England
- NIHR Cambridge Biomedical Research Centre
- Common Fund
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Keywords
- somatic mutations, SF3B1, SRSF2, spliceosome mutations, aging, clonal expansion, myelodysplastic syndrome, mutational hotspots, hematopoietic stem cells
- MeSH terms
- Serine-Arginine Splicing Factors, RNA Splicing Factors, DNA Methyltransferase 3A, Adolescent, Adult, Aged, Aged, 80 and over, Aging, DNA (Cytosine-5-)-Methyltransferases, Hematopoiesis, Humans, Leukemia, Middle Aged, Mutation, Myelodysplastic Syndromes, Nuclear Proteins, Phosphoproteins, Ribonucleoproteins, Ribonucleoprotein, U2 Small Nuclear, Sequence Analysis, DNA, Computational Biology, Young Adult, High-Throughput Nucleotide Sequencing
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