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Modeling the evolutionary dynamics of clonal hematopoiesis

Nature Genetics (2026)Cite this article

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Abstract

Clonal hematopoiesis (CH) results from the acquisition and expansion of somatic mutations in hematopoietic stem and progenitor cells and is associated with age-related clinical sequelae, including an increased risk for cardiovascular disease, myeloid neoplasms and complications related to cancer therapy. Chemotherapy and radiation can accelerate CH expansion and further elevate the risk of adverse events, including cardiotoxicity and therapy-related myeloid neoplasms. Although CH is increasingly recognized as a clinically relevant precursor state and predictive biomarker, the long-term dynamics of CH expansion in humans remain poorly understood. Longitudinal data are often collected but not integrated with mathematical prediction. Mathematical modeling is essential for characterizing CH evolution, estimating clone fitness, inferring stem cell pool dynamics and enabling patient-level predictions. This study summarizes the current evidence on CH dynamics in humans, compares mathematical models used to predict CH progression, assesses the validity of model assumptions and discusses the implications for clinical management of individuals with these precursor conditions.

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Fig. 1: Disruption of normal hematopoiesis and the evolution of myeloid precursor disease.
Fig. 2: Modeling clonal dynamics in hematopoiesis using the Moran process under different evolutionary scenarios.
Fig. 3: Evolutionary dynamics of CH—prevalence, growth models, drift versus selection and multiclonal competition.
Fig. 4: Clonal expansion dynamics during ontogeny and homeostasis, highlighting resulting VAF distributions.

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Acknowledgements

The authors gratefully acknowledge funding from Moffitt Cancer Center via the Center of Excellence for Evolutionary Therapy (to S.M. and J.W.). N.V.M.P. acknowledges support from the Barts Charity. B.W. is supported by a Barts Charity Lectureship (grant MGU045) and a UKRI Future Leaders Fellowship (grant MR/V02342X/1). T.S., J.S. and J.G.H. acknowledge support from the Lundbeck Foundation (grant R335-2019-2020).

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Authors and Affiliations

  1. Integrated Mathematical Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Sadegh Marzban & Jeffrey West

  2. Center for Mathematical Modeling—Human Health and Disease, Roskilde University, Roskilde, Denmark

    Thomas Stiehl, Morten Andersen, Jordan Snyder, Johanne Gudmand-Høyer & Johnny T. Ottesen

  3. Institute for Computational Biomedicine and Disease Modeling, RWTH Aachen University Hospital, Aachen, Germany

    Thomas Stiehl

  4. Department of Malignant Hematology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Zhuoer Xie, Eric Padron & Nancy Gillis

  5. Barts Cancer Institute, Queen Mary University of London, London, UK

    Nathaniel V. Mon Père & Benjamin Werner

  6. School of Mathematical Sciences, Queen Mary University of London, London, UK

    Weini Huang

  7. Division of Hematologic Malignancies, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA

    Amy E. DeZern

  8. Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA

    Mikkael A. Sekeres

  9. Department of Medicine, Washington University, St. Louis, MO, USA

    Matthew J. Walter

  10. Department of Cancer Epidemiology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Nancy Gillis

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Contributions

S.M. designed the figures, with help from N.V.M.P., B.W., W.H. and J.W. All authors contributed to the writing, reviewing and editing of the manuscript.

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Correspondence to Jeffrey West.

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Marzban, S., Stiehl, T., Xie, Z. et al. Modeling the evolutionary dynamics of clonal hematopoiesis. Nat Genet (2026). https://doi.org/10.1038/s41588-026-02504-2

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