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Prediction of acute myeloid leukaemia risk in healthy individuals
Open accessAbstract
The incidence of acute myeloid leukaemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 65. Most cases arise without any detectable early symptoms and patients usually present with the acute complications of bone marrow failure 1. The onset of such de novo AML cases is typically preceded by the accumulation of somatic mutations in preleukaemic haematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion 2,3. However, recurrent AML mutations also accumulate in HSPCs during ageing of healthy individuals who do not develop AML, a phenomenon referred to as age-related clonal haematopoiesis (ARCH)4-8. Here we use deep sequencing to analyse genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign ARCH. We analysed peripheral blood cells from 95 individuals that were obtained on average 6.3 years before AML diagnosis (pre-AML group), together with 414 unselected age- and gender-matched individuals (control group). Pre-AML cases were distinct from controls and had more mutations per sample, higher variant allele frequencies, indicating greater clonal expansion, and showed enrichment of mutations in specific genes. Genetic parameters were used to derive a model that accurately predicted AML-free survival; this model was validated in an independent cohort of 29 pre-AML cases and 262 controls. Because AML is rare, we also developed an AML predictive model using a large electronic health record database that identified individuals at greater risk. Collectively our findings provide proof-of-concept that it is possible to discriminate ARCH from pre-AML many years before malignant transformation. This could in future enable earlier detection and monitoring, and may help to inform intervention.
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“Furthermore, progression to hematological malignancies depends on the type and complexity of mutations in CHIP.2,5,6”
From Aging drives Tet2 +/− clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [5]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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 [34]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“CH prominently involves variants of epigenetic regulatory genes, such as DNMT3A and TET2, which constitute an increased risk for hematologic malignancies, cardiovascular events and stroke 34,45,70,71 .”
From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [34]
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In the citing paper
“Clone size, which is approximated by the variant allele fraction (VAF), has previously been shown to be an important predictor of risk for blood cancer1,17 and cardiovascular outcomes8,9.”
From Clonal hematopoiesis is associated with protection from Alzheimer’s disease (2023) · cites this paper as [17]
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“CH prominently involves variants of epigenetic regulatory genes, such as DNMT3A and TET2, which constitute an increased risk for hematologic malignancies, cardiovascular events and stroke 34,45,70,71 .”
From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [34]
In the citing paper
“Both groups found that individuals with antecedent clonal hematopoiesis were at ~3 to 5-fold increased risk for developing AML in the subsequent years (Fig. 3A).”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [71]
In the citing paper
“The effect of specific gene variants on various outcomes may be quite different, as has been found in AML 71.”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [71]
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Citations
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Cited by
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Clonal hematopoiesis in human aging and disease
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“M. A. Sanders et al., MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML.”
InfluentialFundamental Mechanisms of Regulated Cell Death and Implications for Heart Disease
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Cancer therapy shapes the fitness landscape of clonal hematopoiesis
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Metadata
- Authors
- Abelson, S., Collord, G., Ng, S. W. K., Weissbrod, O., Mendelson Cohen, N., Niemeyer, E., Barda, N., Zuzarte, P. C., Heisler, L., Sundaravadanam, Y., Luben, R., Hayat, S., Wang, T. T., Zhao, Z., Cirlan, I., Pugh, T. J., Soave, D., Ng, K., Latimer, C., Hardy, C., Raine, K., Jones, D., Hoult, D., Britten, A., McPherson, J. D., Johansson, M., Mbabaali, F., Eagles, J., Miller, J. K., Pasternack, D., Timms, L., Krzyzanowski, P., Awadalla, P., Costa, R., Segal, E., Bratman, S. V., Beer, P., Behjati, S., Martincorena, I., Wang, J. C. Y., Bowles, K. M., Quirós, J. R., Karakatsani, A., La Vecchia, C., Trichopoulou, A., Salamanca-Fernández, E., Huerta, J. M., Barricarte, A., Travis, R. C., Tumino, R., Masala, G., Boeing, H., Panico, S., Kaaks, R., Krämer, A., Sieri, S., Riboli, E., Vineis, P., Foll, M., McKay, J., Polidoro, S., Sala, N., Khaw, K.-T., Vermeulen, R., Campbell, P. J., Papaemmanuil, E., Minden, M. D., Tanay, A., Balicer, R. D., Wareham, N. J., Gerstung, M., Dick, J. E., Brennan, P., Vassiliou, G. S., & Shlush, L. I.
- Affiliations
- University Health Network (CA)
- University of Cambridge (GB)
- University of Toronto (CA)
- Weizmann Institute of Science (IL)
- Clalit Health Services (IL)
- Ontario Institute for Cancer Research (CA)
- Wellcome Sanger Institute (GB)
- Centre international de recherche sur le cancer (FR)
- European Bioinformatics Institute (GB)
- University of East Anglia (GB)
- Gobierno del Principado de Asturias (ES)
- National and Kapodistrian University of Athens (GR)
- Hellenic Health Foundation (GR)
- Instituto Murciano de Investigación Biosanitaria (ES)
- Instituto de Salud Pública de Navarra (ES)
- University of Oxford (GB)
- Istituto per lo Studio e la Prevenzione Oncologica (IT)
- German Institute of Human Nutrition (DE)
- Federico II University Hospital (IT)
- German Cancer Research Center (DE)
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
- Imperial College London (GB)
- Italian institute for Genomic Medicine (IT)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Utrecht University (NL)
- Memorial Sloan Kettering Cancer Center (US)
- World Health Organization (CH)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Corresponding author
- Gerstung, Moritz
- Dick, John E.
- Brennan, Paul
- Vassiliou, George S.
- Shlush, Liran I.
- ORCID
- Abelson, Sagi
- Collord, Grace
- Ng, Stanley W. K.
- Weissbrod, Omer
- Barda, Noam
- Zuzarte, Philip C.
- Heisler, Lawrence
- Sundaravadanam, Yogi
- Luben, Robert
- Hayat, Shabina
- Zhao, Zhen
- Cirlan, Iulia
- Pugh, Trevor J.
- Soave, David
- Ng, Karen
- Latimer, Calli
- Raine, Keiran
- Jones, David
- Britten, Abigail
- McPherson, John D.
- Johansson, Mattias
- Eagles, Jenna
- Miller, Jessica K.
- Krzyzanowski, Paul
- Awadalla, Philip
- Costa, Rui
- Segal, Eran
- Bratman, Scott V.
- Beer, Philip
- Behjati, Sam
- Wang, Jean C. Y.
- Bowles, Kristian M.
- Karakatsani, Anna
- Trichopoulou, Antonia
- Huerta, José M.
- Barricarte, Aurelio
- Travis, Ruth C.
- Tumino, Rosario
- Masala, Giovanna
- Boeing, Heiner
- Panico, Salvatore
- Kaaks, Rudolf
- Krämer, Alwin
- Sieri, Sabina
- Vineis, Paolo
- Foll, Matthieu
- McKay, James
- Polidoro, Silvia
- Sala, Núria
- Khaw, Kay-Tee
- Vermeulen, Roel
- Campbell, Peter J.
- Papaemmanuil, Elli
- Minden, Mark D.
- Tanay, Amos
- Balicer, Ran D.
- Wareham, Nicholas J.
- Gerstung, Moritz
- Dick, John E.
- Brennan, Paul
- Vassiliou, George S.
- Shlush, Liran I.
- Venue
- Nature
- Published
- 2018-07
- Volume
- 559
- Issue
- 7714
- Pages
- 400-404
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6485381
- OpenAlex
- W2830196912
- Cited by
- 850
- References
- 49
- Citations by year
- 2026: 52 · 2025: 83 · 2024: 95 · 2023: 116 · 2022: 122 · 2021: 116 · 2020: 143 · 2019: 91 · 2018: 29
- FWCI
- 67.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RISalud Institutional Health Repository of Andalucía (submittedVersion, public-domain)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Apollo
- Funders
- World Health Organization
- Leukemia and Lymphoma Society
- Wellcome Trust (WT 098051, WT095663MA)
- Cancer Research UK (23015, 14136, 16491, 21777)
- National Institute for Health and Care Research (NF-SI-0512-10114, NF-SI-0512-10135, NF-SI-0617-10149)
- Generalitat de Catalunya
- Associazione Italiana per la Ricerca sul Cancro
- Clalit Health Services
- Abisch-Frenkel-Stiftung
- Hellenic Health Foundation
- Medical Research Council (MC_UU_12015/1, MC_PC_13048, MC_PC_12009, MR/N003284/1)
- Agència de Gestió d'Ajuts Universitaris i de Recerca
- Instituto de Salud Carlos III (RD12/0036/0018)
- European Regional Development Fund
- National Cancer Institute (P30CA008748)
- 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 › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- acute myeloid leukemia, somatic mutations, clonal expansion, variant allele frequency
- MeSH terms
- Adult, Age Factors, Aged, Female, Health, Humans, Male, Middle Aged, Models, Genetic, Mutation, Leukemia, Myeloid, Acute, Prevalence, Mutagenesis, Disease Progression, Risk Assessment, Genetic Predisposition to Disease, Electronic Health Records
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