Abstract
Clonal hematopoiesis (CH) results from clonal expansion of hematopoietic stem cells. In specific contexts, CH is linked with an increased risk of blood cancers and mortality in individuals with solid tumors. To understand the mechanisms and clinical relevance of this association, it is crucial to explore the reciprocal relationship between CH and cancer. Here, we provide an updated summary of the mechanisms known to drive CH in blood cancers and solid tumors. In addition, we review proposed strategies to intercept CH and examine their impact on solid tumor-directed therapies, including immunostimulatory therapies.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$32.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 digital issues and online access to articles
$119.00 per year
only $9.92 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Kanagal-Shamanna, R., Beck, D. B. & Calvo, K. R. Clonal hematopoiesis, inflammation, and hematologic malignancy. Annu. Rev. Pathol. 19, 479–506 (2024).
Ayachi, S., Buscarlet, M. & Busque, L. 60 Years of clonal hematopoiesis research: from X-chromosome inactivation studies to the identification of driver mutations. Exp. Hematol. 83, 2–11 (2020).
Warren, J. T. & Link, D. C. Clonal hematopoiesis and risk for hematologic malignancy. Blood 136, 1599–1605 (2020).
Coombs, C. C. et al. Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell 21, 374–382 (2017).
Pedersen, R. K., Andersen, M., Stiehl, T. & Ottesen, J. T. Mathematical modelling of the hematopoietic stem cell-niche system: clonal dominance based on stem cell fitness. J. Theor. Biol. 518, 110620 (2021).
Tothova, Z. et al. Multiplex CRISPR/Cas9-based genome editing in human hematopoietic stem cells models clonal hematopoiesis and myeloid neoplasia. Cell Stem Cell 21, 547–555 (2017).
Kapadia, C. D. et al. Clonal hematopoiesis in mice is common with age and accelerated by microbial exposure. Blood 140, 5741–5742 (2022).
Buttigieg, M. M. & Rauh, M. J. Clonal hematopoiesis: updates and implications at the solid tumor–immune interface. JCO Precis. Oncol. 7, e2300132 (2023).
Singh, A. & Balasubramanian, S. The crossroads of cancer therapies and clonal hematopoiesis. Semin. Hematol. 61, 16–21 (2024).
Takahashi, K., Nakada, D. & Goodell, M. Distinct landscape and clinical implications of therapy-related clonal hematopoiesis. J. Clin. Invest. https://doi.org/10.1172/JCI180069 (2024).
Evans, M. A. & Walsh, K. Clonal hematopoiesis, somatic mosaicism, and age-associated disease. Physiol. Rev. 103, 649–716 (2023).
Linder, D. & Gartler, S. M. Glucose-6-phosphate dehydrogenase mosaicism: utilization as a cell marker in the study of leiomyomas. Science 150, 67–69 (1965).
Beutler, E., Yeh, M. & Fairbanks, V. F. The normal human female as a mosaic of X-chromosome activity: studies using the gene for C-6-PD-deficiency as a marker. Proc. Natl Acad. Sci. USA 48, 9–16 (1962).
Busque, L. et al. Skewing of X-inactivation ratios in blood cells of aging women is confirmed by independent methodologies. Blood 113, 3472–3474 (2009).
Busque, L. et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat. Genet. 44, 1179–1181 (2012).
Genovese, G. et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371, 2477–2487 (2014).
Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014).
Guermouche, H. et al. High prevalence of clonal hematopoiesis in the blood and bone marrow of healthy volunteers. Blood Adv. 4, 3550–3557 (2020).
Jacobs, K. B. et al. Detectable clonal mosaicism and its relationship to aging and cancer. Nat. Genet. 44, 651–658 (2012).
Fabre, M. A. et al. The longitudinal dynamics and natural history of clonal haematopoiesis. Nature 606, 335–342 (2022).
Young, A. L., Challen, G. A., Birmann, B. M. & Druley, T. E. Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat. Commun. 7, 12484 (2016).
Xie, M. et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat. Med. 20, 1472–1478 (2014).
Comen, E. A. et al. Evaluating clonal hematopoiesis in tumor-infiltrating leukocytes in breast cancer and secondary hematologic malignancies. J. Natl Cancer Inst. 112, 107–110 (2020).
Kleppe, M. et al. Somatic mutations in leukocytes infiltrating primary breast cancers. NPJ Breast Cancer 1, 15005 (2015).
Ptashkin, R. N. et al. Prevalence of clonal hematopoiesis mutations in tumor-only clinical genomic profiling of solid tumors. JAMA Oncol. 4, 1589–1593 (2018).
Coombs, C. C. et al. Identification of clonal hematopoiesis mutations in solid tumor patients undergoing unpaired next-generation sequencing assays. Clin. Cancer Res. 24, 5918–5924 (2018).
Ruark, E. et al. Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature 493, 406–410 (2013).
Bowman, R. L., Busque, L. & Levine, R. L. Clonal hematopoiesis and evolution to hematopoietic malignancies. Cell Stem Cell 22, 157–170 (2018).
Bernstein, N. et al. Analysis of somatic mutations in whole blood from 200,618 individuals identifies pervasive positive selection and novel drivers of clonal hematopoiesis. Nat. Genet. 56, 1147–1155 (2024).
Weeks, L. D. & Ebert, B. L. Causes and consequences of clonal hematopoiesis. Blood 142, 2235–2246 (2023).
Abelson, S. et al. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature 559, 400–404 (2018).
Gallì, A. et al. Relationship between clone metrics and clinical outcome in clonal cytopenia. Blood 138, 965–976 (2021).
Weeks, L. D. et al. Prediction of risk for myeloid malignancy in clonal hematopoiesis. NEJM Evid. https://doi.org/10.1056/evidoa2200310 (2023).
Mitchell, E. et al. Clonal dynamics of haematopoiesis across the human lifespan. Nature 606, 343–350 (2022).
Pich, O., Reyes-Salazar, I., Gonzalez-Perez, A. & Lopez-Bigas, N. Discovering the drivers of clonal hematopoiesis. Nat. Commun. https://doi.org/10.1038/s41467-022-31878-0 (2022).
Osorio, F. G. et al. Somatic mutations reveal lineage relationships and age-related mutagenesis in human hematopoiesis. Cell Rep. 25, 2308–2316 (2018).
Cagan, A. et al. Somatic mutation rates scale with lifespan across mammals. Nature 604, 517–524 (2022).
Spisak, N., de Manuel, M., Milligan, W., Sella, G. & Przeworski, M. The clock-like accumulation of germline and somatic mutations can arise from the interplay of DNA damage and repair. PLoS Biol. 22, e3002678 (2024).
Vijg, J. From DNA damage to mutations: all roads lead to aging. Ageing Res. Rev. 68, 101316 (2021).
Fuster, J. J. & Walsh, K. Somatic mutations and clonal hematopoiesis: unexpected potential new drivers of age-related cardiovascular disease. Circ. Res. 122, 523–532 (2018).
Feldman, T. et al. Recurrent deletions in clonal hematopoiesis are driven by microhomology-mediated end joining. Nat. Commun. 12, 2455 (2021).
Vijg, J. et al. Mitigating age-related somatic mutation burden. Trends Mol. Med. 29, 530–540 (2023).
Aitken, S. J. et al. Pervasive lesion segregation shapes cancer genome evolution. Nature 583, 265–270 (2020).
Spencer Chapman, M. et al. Prolonged persistence of mutagenic DNA lesions in somatic cells. Nature https://doi.org/10.1038/s41586-024-08423-8 (2025).
Uryu, H. et al. Clonal evolution of hematopoietic stem cells after cancer chemotherapy. Preprint at bioRxiv https://doi.org/10.1101/2024.05.23.595594 (2024).
Biechonski, S. et al. Attenuated DNA damage responses and increased apoptosis characterize human hematopoietic stem cells exposed to irradiation. Sci. Rep. 8, 6071 (2018).
Milyavsky, M. et al. A distinctive DNA damage response in human hematopoietic stem cells reveals an apoptosis-independent role for p53 in self-renewal. Cell Stem Cell 7, 186–197 (2010).
Mohrin, M. et al. Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis. Cell Stem Cell 7, 174–185 (2010).
Yamashita, N. et al. Loss of Nudt15 thiopurine detoxification increases direct DNA damage in hematopoietic stem cells. Sci. Rep. 13, 11908 (2023).
Marshall, C. H. et al. Association of PARP inhibitor treatment on the prevalence and progression of clonal hematopoiesis in patients with advanced prostate cancer. Prostate 84, 954–958 (2024).
Kwan, T. T. et al. Preexisting TP53-variant clonal hematopoiesis and risk of secondary myeloid neoplasms in patients with high-grade ovarian cancer treated with rucaparib. JAMA Oncol. 7, 1772–1781 (2021).
Guryanova, O. A. et al. DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. Nat. Med. 22, 1488–1495 (2016).
Caiado, F., Pietras, E. M. & Manz, M. G. Inflammation as a regulator of hematopoietic stem cell function in disease, aging, and clonal selection. J. Exp. Med. https://doi.org/10.1084/jem.20201541 (2021).
Zhao, J., Ghimire, A. & Liesveld, J. Marrow failure and aging: the role of ‘inflammaging’. Best Pract. Res. Clin. Haematol. 34, 101283 (2021).
SanMiguel, J. M. et al. Distinct tumor necrosis factor α receptors dictate stem cell fitness versus lineage output in Dnmt3a-mutant clonal hematopoiesis. Cancer Discov. 12, 2763–2773 (2022).
Abegunde, S. O., Buckstein, R., Wells, R. A. & Rauh, M. J. An inflammatory environment containing TNFα favors Tet2-mutant clonal hematopoiesis. Exp. Hematol. 59, 60–65 (2018).
Young, K. et al. Decline in IGF1 in the bone marrow microenvironment initiates hematopoietic stem cell aging. Cell Stem Cell 28, 1473–1482 (2021).
Jakobsen, N. A. et al. Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging. Cell Stem Cell 31, 1127–1144 (2024).
Buttlar, A. Rehabilitation overseas. Integration of handicapped students at American community colleges (in German). Rehabilitation (Stuttg.) 27, 221–227 (1988).
Caiado, F. et al. Aging drives Tet2+/− clonal hematopoiesis via IL-1 signaling. Blood 141, 886–903 (2023).
Hormaechea-Agulla, D. et al. Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling. Cell Stem Cell 28, 1428–1442 (2021).
Cook, E. K., Luo, M. & Rauh, M. J. Clonal hematopoiesis and inflammation: partners in leukemogenesis and comorbidity. Exp. Hematol. 83, 85–94 (2020).
Gibson, C. J. et al. Clonal hematopoiesis associated with adverse outcomes after autologous stem-cell transplantation for lymphoma. J. Clin. Oncol. 35, 1598–1605 (2017).
Yan, C. et al. Clonal hematopoiesis and therapy-related myeloid neoplasms after autologous transplant for Hodgkin lymphoma. J. Clin. Oncol. 42, 2415–2424 (2024).
Hasserjian, R. P., Steensma, D. P., Graubert, T. A. & Ebert, B. L. Clonal hematopoiesis and measurable residual disease assessment in acute myeloid leukemia. Blood 135, 1729–1738 (2020).
Gibson, C. J. et al. Donor clonal hematopoiesis and recipient outcomes after transplantation. J. Clin. Oncol. 40, 189–201 (2022).
Kim, K. H. et al. Clonal hematopoiesis in the donor does not adversely affect long-term outcomes following allogeneic hematopoietic stem cell transplantation: result from a 13-year follow-up. Haematologica 108, 1817–1826 (2023).
Oshima, M. U. et al. Characterization of clonal dynamics using duplex sequencing in donor–recipient pairs decades after hematopoietic cell transplantation. Sci. Transl. Med. 16, eado5108 (2024).
Spencer Chapman, M. et al. Clonal dynamics after allogeneic haematopoietic cell transplantation. Nature 635, 926–934 (2024).
Oran, B. et al. Donor clonal hematopoiesis increases risk of acute graft versus host disease after matched sibling transplantation. Leukemia 36, 257–262 (2022).
DeZern, A. E. & Gondek, L. P. Stem cell donors should be screened for CHIP. Blood Adv. 4, 784–788 (2020).
Gibson, C. J. & Lindsley, R. C. Stem cell donors should not be screened for clonal hematopoiesis. Blood Adv. 4, 789–792 (2020).
Jasra, S. et al. High burden of clonal hematopoiesis in first responders exposed to the World Trade Center disaster. Nat. Med. 28, 468–471 (2022).
Bolton, K. L. et al. Clonal hematopoiesis is associated with risk of severe Covid-19. Nat. Commun. 12, 5975 (2021).
Zhou, Y. et al. Clonal hematopoiesis is not significantly associated with COVID-19 disease severity. Blood 140, 1650–1655 (2022).
Zink, F. et al. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 130, 742–752 (2017).
Ganuza, M. et al. The global clonal complexity of the murine blood system declines throughout life and after serial transplantation. Blood 133, 1927–1942 (2019).
Weng, C. et al. Deciphering cell states and genealogies of human haematopoiesis. Nature 627, 389–398 (2024).
Desai, P. et al. Somatic mutations precede acute myeloid leukemia years before diagnosis. Nat. Med. 24, 1015–1023 (2018).
Aiman, W. et al. Efficacy and tolerability of isocitrate dehydrogenase inhibitors in patients with acute myeloid leukemia: a systematic review of clinical trials. Leuk. Res. 129, 107077 (2023).
Steensma, D. P. The clinical challenge of idiopathic cytopenias of undetermined significance (ICUS) and clonal cytopenias of undetermined significance (CCUS). Curr. Hematol. Malig. Rep. 14, 536–542 (2019).
Dutta, R. et al. Enasidenib drives human erythroid differentiation independently of isocitrate dehydrogenase 2. J. Clin. Invest. 130, 1843–1849 (2020).
Toma, M. M. et al. Clonal medicine targeting DNA damage response eradicates leukemia. Leukemia 38, 671–675 (2024).
Maifrede, S. et al. TET2 and DNMT3A mutations exert divergent effects on DNA repair and sensitivity of leukemia cells to PARP inhibitors. Cancer Res. 81, 5089–5101 (2021).
Kahn, J. D. et al. PPM1D-truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells. Blood 132, 1095–1105 (2018).
Waarts, M. R. et al. CRISPR dependency screens in primary hematopoietic stem cells identify KDM3B as a genotype-specific vulnerability in IDH2- and TET2-mutant cells. Cancer Discov. 14, 1860–1878 (2024).
Gozdecka, M. et al. Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis. Nature https://doi.org/10.1038/s41586-025-08980-6 (2025).
Hosseini, M. et al. Metformin reduces the competitive advantage of Dnmt3aR878H HSPCs. Nature https://doi.org/10.1038/s41586-025-08871-w (2025).
Young, K. A. et al. Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis. Nat. Commun. 16, 3306 (2025).
Fuster, J. J. et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355, 842–847 (2017).
Azrakhsh, N. A., Mensah-Glanowska, P., Sand, K. & Kittang, A. O. Targeting immune signaling pathways in clonal hematopoiesis. Curr. Med. Chem. 26, 5262–5277 (2019).
Shin, T.-H. et al. A macaque clonal hematopoiesis model demonstrates expansion of TET2-disrupted clones and utility for testing interventions. Blood 140, 1774–1789 (2022).
Svensson, E. C. et al. TET2-driven clonal hematopoiesis and response to canakinumab: an exploratory analysis of the CANTOS randomized clinical trial. JAMA Cardiol. 7, 521–528 (2022).
Grebe, A., Hoss, F. & Latz, E. NLRP3 inflammasome and the IL-1 pathway in atherosclerosis. Circ. Res. 122, 1722–1740 (2018).
Kapadia, C. D. et al. Clonal dynamics and somatic evolution of haematopoiesis in mouse. Nature 641, 681–689 (2025).
Boucai, L. et al. Radioactive iodine-related clonal hematopoiesis in thyroid cancer is common and associated with decreased survival. J. Clin. Endocrinol. Metab. 103, 4216–4223 (2018).
Tian, R. et al. Clonal hematopoiesis and risk of incident lung cancer. J. Clin. Oncol. 41, 1423–1433 (2023).
Tiedje, V. et al. Targetable treatment resistance in thyroid cancer with clonal hematopoiesis. Preprint at bioRxiv https://doi.org/10.1101/2024.10.10.617685 (2024).
Diplas, B. H. et al. Clinical importance of clonal hematopoiesis in metastatic gastrointestinal tract cancers. JAMA Netw. Open 6, e2254221 (2023).
Liu, X. et al. CHIP-associated mutant ASXL1 in blood cells promotes solid tumor progression. Cancer Sci. 113, 1182–1194 (2022).
Gibson, C. J. et al. Clonal hematopoiesis in young women treated for breast cancer. Clin. Cancer Res. 29, 2551–2558 (2023).
Morganti, S. et al. Prevalence, dynamics, and prognostic role of clonal hematopoiesis of indeterminate potential in patients with breast cancer. J. Clin. Oncol. https://doi.org/10.1200/jco.23.01071 (2024).
Uyanik, B. et al. Inhibition of the DNA damage response phosphatase PPM1D reprograms neutrophils to enhance anti-tumor immune responses. Nat. Commun. 12, 3622 (2021).
Mukohara, F. et al. Somatic mutations in tumor-infiltrating lymphocytes impact on antitumor immunity. Proc. Natl Acad. Sci. USA 121, e2320189121 (2024).
Severson, E. A. et al. Detection of clonal hematopoiesis of indeterminate potential in clinical sequencing of solid tumor specimens. Blood 131, 2501–2505 (2018).
Li, S. et al. TET2 promotes anti-tumor immunity by governing G-MDSCs and CD8+ T-cell numbers. EMBO Rep. 21, e49425 (2020).
Pan, W. et al. The DNA methylcytosine dioxygenase Tet2 sustains immunosuppressive function of tumor-infiltrating myeloid cells to promote melanoma progression. Immunity 47, 284–297 (2017).
Feng, Y. et al. Hematopoietic-specific heterozygous loss of Dnmt3a exacerbates colitis-associated colon cancer. J. Exp. Med. https://doi.org/10.1084/jem.20230011 (2023).
Nguyen, Y. T. M. et al. Tet2 deficiency in immune cells exacerbates tumor progression by increasing angiogenesis in a lung cancer model. Cancer Sci. 112, 4931–4943 (2021).
Bolton, K. L. et al. Managing clonal hematopoiesis in patients with solid tumors. J. Clin. Oncol. 37, 7–11 (2019).
Hsu, J. I. et al. PPM1D mutations drive clonal hematopoiesis in response to cytotoxic chemotherapy. Cell Stem Cell 23, 700–713 (2018).
Prinzing, B. et al. Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity. Sci. Transl. Med. 13, eabh0272 (2021).
Fraietta, J. A. et al. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 558, 307–312 (2018).
Nobles, C. L. et al. CD19-targeting CAR T cell immunotherapy outcomes correlate with genomic modification by vector integration. J. Clin. Invest. 130, 673–685 (2020).
Tolcher, A. W. et al. Phase I study of GS-3583, an FMS-like tyrosine kinase 3 agonist Fc fusion protein, in patients with advanced solid tumors. Clin. Cancer Res. 30, 2954–2963 (2024).
Dillon, L. W. et al. DNA sequencing to detect residual disease in adults with acute myeloid leukemia prior to hematopoietic cell transplant. JAMA 329, 745–755 (2023).
Aggarwal, C. et al. Assessment of tumor mutational burden and outcomes in patients with diverse advanced cancers treated with immunotherapy. JAMA Netw. Open 6, e2311181 (2023).
Bolton, K. L. et al. The clinical management of clonal hematopoiesis: creation of a clonal hematopoiesis clinic. Hematol. Oncol. Clin. North Am. 34, 357–367 (2020).
Haque, T. et al. A blueprint for pursuing therapeutic interventions and early phase clinical trials in clonal haematopoiesis. Br. J. Haematol. 206, 416–427 (2025).
Steensma, D. P. & Bolton, K. L. What to tell your patient with clonal hematopoiesis and why: insights from 2 specialized clinics. Blood 136, 1623–1631 (2020).
Acknowledgements
J.J.T. is supported by the National Institutes of Health (grants R01DK118072, R01AG069010 and U01AG077925). J.J.T. is a scholar of the Leukemia & Lymphoma Society. X.C. holds a scholar award from The Jackson Laboratory. R.L.B. is supported by the National Cancer Institute (R00CA248460) and the Leukemia Research Foundation. R.L.B. is a scholar of the American Society of Hematology.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Cancer thanks Liran Shlush, Paresh Vyas and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Cai, X., Bowman, R.L. & Trowbridge, J.J. Clonal hematopoiesis in myeloid malignancies and solid tumors. Nat Cancer 6, 1133–1144 (2025). https://doi.org/10.1038/s43018-025-01014-0
Received:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s43018-025-01014-0