Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults
Open accessAbstract
Clonal haematopoiesis is thought to be a rare condition that increases in frequency with age and predisposes individuals to haematological malignancy. Recent studies, utilizing next-generation sequencing (NGS), observed haematopoietic clones in 10% of 70-year olds and rarely in younger individuals. However, these studies could only detect common haematopoietic clones->0.02 variant allele fraction (VAF)-due to the error rate of NGS. To identify and characterize clonal mutations below this threshold, here we develop methods for targeted error-corrected sequencing, which enable the accurate detection of clonal mutations as rare as 0.0003 VAF. We apply these methods to study serially banked peripheral blood samples from healthy 50-60-year-old participants in the Nurses' Health Study. We observe clonal haematopoiesis, frequently harbouring mutations in DNMT3A and TET2, in 95% of individuals studied. These clonal mutations are often stable longitudinally and present in multiple haematopoietic compartments, suggesting a long-lived haematopoietic stem and progenitor cell of origin.
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DNMT3A is the gene most commonly mutated in clonal hematopoiesis.
“DNMT3A, the gene most commonly mutated in CH”
From Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling (2021) · cites this paper as Young et al., 2016
The Results (Error-corrected NGS; page unavailable) report that 64% of exonic clonal variants occurred in DNMT3A and TET2 combined. The Discussion says DNMT3A mutations are frequent in clonal haematopoiesis, but the paper does not establish that DNMT3A alone is the most commonly mutated gene. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDNMT3A mutations are nearly universal in individuals by the age of 50.
“mutations in DNMT3A, the gene most commonly mutated in CH, are nearly universal in individuals by the age of 50 (Young et al., 2016)”
From Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling (2021) · cites this paper as Young et al., 2016
The Abstract (page unavailable) reports clonal haematopoiesis in 95% of the healthy 50–60-year-olds studied, with mutations frequently in DNMT3A or TET2. The Results (Error-corrected NGS; page unavailable) show DNMT3A is a frequent mutation site, but the paper does not say DNMT3A mutations themselves are nearly universal, or establish that they are present by age 50. (LLM, conf=0.90)
Experimental — accuracy not yet measuredSomatic DNMT3A variants become almost ubiquitous in the aging population.
“Emerging evidence indicates somatic DNMT3A variants can be acquired early in life (12,13), before becoming almost ubiquitous in the aging population (14).”
From <i>Txnip</i> Enhances Fitness of <i>Dnmt3a</i> -Mutant Hematopoietic Stem Cells via <i>p21</i> (2022) · cites this paper as [14]
The Abstract reports clonal haematopoiesis in 95% of the healthy adults studied and says those clones frequently harboured DNMT3A and TET2 mutations. The Discussion describes near ubiquity for clones with mutations in AML-associated genes, not for DNMT3A variants specifically. The study’s age range also does not establish prevalence across the aging population generally. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCH mutations occur in early multipotent progenitors, possibly HSPCs.
“The CH mutations occur in early multipotent progenitors, possibly HSPCs, because mutational analyses of lymphoid and myeloid cells have confirmed the presence of the same variants [19].”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [19]
If sequenced deeply enough, a cancer-associated mutation may be detectable in most people over the age of 50.
“If sequenced deeply enough, a cancer-associated mutation may be detectable in most people over the age of 50 33,”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [33]
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 [33]
Some people have clones that remain stagnant in size for many years, whereas other people have clones that show steady growth.
“Some people have clones that remain stagnant in size for many years, whereas other people have clones that show steady growth 28,33.”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [33]
Studies of serial samples have shown that the trajectory of a clone can vary between people.
“Studies of serial samples have shown that the trajectory of a clone can vary between people.”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [33]
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Clonal hematopoiesis in human aging and disease
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“Some people have clones that remain stagnant in size for many years, whereas other people have clones that show steady growth (29, 34).”
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- Authors
- Young, A. L., Challen, G. A., Birmann, B. M., & Druley, T. E.
- Affiliations
- Washington University in St. Louis (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Druley, Todd E.
- Venue
- Nature Communications
- Published
- 2016-08-22
- Volume
- 7
- Issue
- 1
- Pages
- 12484-12484
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4996934
- OpenAlex
- W2511116391
- Cited by
- 692
- References
- 44
- Citations by year
- 2026: 41 · 2025: 52 · 2024: 72 · 2023: 82 · 2022: 90 · 2021: 89 · 2020: 91 · 2019: 69 · 2018: 62 · 2017: 38 · 2016: 5
- FWCI
- 55.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Children's Discovery Institute (MC-II-2015-461)
- National Institutes of Health (5r01ca049449-18, R01 CA49449, CA-49449, CA186107)
- National Cancer Institute (R01CA149445, R01‐CA049449, UM1CA186107)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK102428)
- Hyundai Hope On Wheels (2015Q3-3)
- 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, DNMT3A mutation, TET2 mutation, clonal mutations, variant allele frequency, hematopoietic stem and progenitor cells, healthy adults, Nurses' Health Study
- MeSH terms
- DNA Methyltransferase 3A, Acute Disease, Aged, Clone Cells, DNA (Cytosine-5-)-Methyltransferases, DNA-Binding Proteins, Female, Gene Frequency, Hematopoiesis, Humans, Leukemia, Myeloid, Middle Aged, Mutation, Proto-Oncogene Proteins, Genetic Variation, Cohort Studies, Genetic Predisposition to Disease, Dioxygenases, High-Throughput Nucleotide Sequencing
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