Inflammatory cytokines promote clonal hematopoiesis with specific mutations in ulcerative colitis patients
Open accessAbstract
Epidemiological sequencing studies have revealed that somatic mutations characteristic of myeloid neoplasms can be detected in the blood of asymptomatic individuals decades prior to presentation of any clinical symptoms. This premalignant condition is known as clonal hematopoiesis of indeterminate potential (CHIP). Despite the fact these mutant clones become readily detectable in the blood of elderly individuals (∼10% of people over the age of 65), the overall rate of disease progression remains relatively low. Thus, in addition to genetic mutations, there are likely environmental factors that contribute to clonal evolution in people with CHIP. One environmental stress that increases with age is inflammation. Although chronic inflammation is detrimental to the long-term function of normal hematopoietic stem cells, several recent studies in animal models have indicated hematopoietic stem cells with CHIP mutations may be resistant to these deleterious effects. However, direct evidence indicating a correlation between increased inflammation and accelerated CHIP in humans is currently lacking. In this study, we sequenced the peripheral blood cells of a cohort of patients with ulcerative colitis, an autoimmune disease characterized by increased levels of pro-inflammatory cytokines. This analysis revealed that the inflammatory environment of ulcerative colitis promoted CHIP with a distinct mutational spectrum, notably positive selection of clones with DNMT3A and PPM1D mutations. We also show a specific association between elevated levels of serum interferon gamma and DNMT3A mutations. These data add to our understanding of how cell extrinsic factors select for clones with specific mutations to promote clonal hematopoiesis.
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No direct experiments have been performed to quantify fitness between mutant and wild-type hematopoietic stem cells in response to IFNγ.
“Although the competitive advantage of Dnmt3a-mutant HSCs during inflammation has been implied (20,23), no direct experiments have been performed to quantify fitness between mutant and WT HSCs in response to IFNγ.”
From <i>Txnip</i> Enhances Fitness of <i>Dnmt3a</i> -Mutant Hematopoietic Stem Cells via <i>p21</i> (2022) · cites this paper as [23]
Ulcerative colitis patients have a higher incidence of DNMT3A-mutant clonal hematopoiesis associated with increased serum IFNγ.
“We recently showed ulcerative colitis patients have a higher incidence of DNMT3A-mutant CH associated with increased serum IFNγ (23).”
From <i>Txnip</i> Enhances Fitness of <i>Dnmt3a</i> -Mutant Hematopoietic Stem Cells via <i>p21</i> (2022) · cites this paper as [23]
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Kishtagari, A., Corty, R. W., & Visconte, V. (2024) · Seminars in Hematology · doi:10.1053/j.seminhematol.2024.01.012 · Cited by 22 · see citing works
Clonal Hematopoiesis of Indeterminate Potential in Crohn’s Disease and Ulcerative Colitis
Selvan, M. E., Nathan, D. I., Guisado, D., Collatuzzo, G., Iruvanti, S., Boffetta, P., Mascarenhas, J. O., Hoffman, R., Cohen, L. J., Marcellino, B. K., et al. (2025) · Inflammatory Bowel Diseases · doi:10.1093/ibd/izae312 · Cited by 20 · see citing works
Tissue mosaicism following stem cell aging: blood as an exemplar
Kapadia, C. D., & Goodell, M. A. (2024) · Nature Aging · doi:10.1038/s43587-024-00589-0 · Cited by 18 · see citing works
“Similarly, DNMT3A -mutant CH was more prevalent in humans with ulcerative colitis 120 , which is associated with systemic inflammation, and in animal models of chronic infection 121 and bone marrow adiposity 122 .”
Clonal hematopoiesis of indeterminate potential and cardiovascular disease
Saadatagah, S., & Ballantyne, C. M. (2022) · Translational research · doi:10.1016/j.trsl.2022.08.013 · Cited by 17 · see citing works
Inflammation in myelodysplastic syndrome pathogenesis
Rodríguez‐Sevilla, J. J., & Colla, S. (2024) · Seminars in Hematology · doi:10.1053/j.seminhematol.2024.09.005 · Cited by 18 · see citing works
Clonal Hematopoiesis of Indeterminate Potential as a Novel Risk Factor for Donor-Derived Leukemia
Burns, S. S., & Kapur, R. (2020) · Stem Cell Reports · doi:10.1016/j.stemcr.2020.07.008 · Cited by 18 · see citing works
“As CHIP ismodulated by comorbidities, other conditions may influence DDL and may account for differences in clinical presentation between donors and recipients (Dragoljevic et al., 2018; Zhang et al., 2019).”
BackgroundA cellular identity crisis? Plasticity changes during aging and rejuvenationPreprint
Gorelov, R. A., & Hochedlinger, K. (2024) · Genes & Development · doi:10.1101/gad.351728.124 · Cited by 18 · see citing works
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Impact of Host, Lifestyle and Environmental Factors in the Pathogenesis of MPN
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Gaulin, C., Kelemen, K., & Yi, C. A. (2022) · Life · doi:10.3390/life12081135 · Cited by 16 · see citing works
Sato, N., Goyama, S., & Kitamura, T. (2025) · International Journal of Hematology · doi:10.1007/s12185-025-04038-5 · Cited by 17 · see citing works
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Kállai, A., Ungvari, A., Csabán, D., Őrfi, Z., Lehoczki, A., Harasztdombi, J., Yabluchanskiy, A., Benyó, Z., Szappanos, Á., Tarantini, S., et al. (2025) · GeroScience · doi:10.1007/s11357-025-01654-1 · Cited by 14 · see citing works
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“Under the influence of inflammatory cytokines, the rates of bone marrow hematopoiesis, erythropoietin production, and iron metabolism process could be altered, which affects the maturation of red blood cells [15, 16].”
BackgroundGurnari, C., & Visconte, V. (2023) · Leukemia Research · doi:10.1016/j.leukres.2023.107038 · Cited by 13 · see citing works
Immune Checkpoint Inhibitor Therapy and Associations with Clonal Hematopoiesis
Singh, A., Mencia-Trinchant, N., Mishra, R., Arora, K., Mehta, S., Kuzmanovic, T., Nikoo, M. Z., Singh, I., Przespolewski, A., Swaminathan, M., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252011049 · Cited by 12 · see citing works
“Analyzing exposures that lead to a selective growth advantage of CH is an active investigational focus [5,6].”
BackgroundLiu, Y., Xi, Z., Zhou, J., Ling, F., Zhang, Y., Xie, H., Zheng, J., Xia, B., Feng, H., & Li, Y. (2025) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-24-1342 · Cited by 12 · see citing works
Du, L., Freitas-Cortez, M. A., Zhang, J., Xue, Y., Veettil, R. T., Zhao, Z., & Morrison, S. J. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2412317122 · Cited by 12 · see citing works
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Self-citationOsman, A. E. G., Mencia-Trinchant, N., Saygin, C., Moma, L., Kim, A., Housman, G., Pozsgai, M. J., Sinha, E., Chandra, P., Hassane, D. C., et al. (2022) · Blood Advances · doi:10.1182/bloodadvances.2022008521 · Cited by 12 · see citing works
“CH is associated with hematologic malignancies,(1-3,7) cardiovascular disease,(8) and inflammatory conditions, including inflammatory bowel disease and vasculitis.(9-12) CH was recently added to the World Health Organization Classification of Haematolymphoid Tumours.”
BackgroundVEXAS syndrome, a new kid on the block of auto-inflammatory diseases: A hematologist's point of view
Heiblig, M., Patel, B. A., & Jamilloux, Y. (2023) · Best Practice & Research Clinical Rheumatology · doi:10.1016/j.berh.2023.101861 · Cited by 12 · see citing works
A 2026 update on myelodysplastic neoplasms: current state, challenges and future directions
Bewersdorf, J. P., Mina, A. A., Stahl, M. F., & Zeidan, A. M. (2026) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-026-01141-2 · Cited by 11 · see citing works
Cacic, A. M., Schulz, F. I., Germing, U., Dietrich, S., & Gattermann, N. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1303785 · Cited by 10 · see citing works
Jensen, J. L., Bobek, O. J., Chan, I. C. C., Miller, B. C., Hillman, D. W., Heller, G., Druley, T. E., Armstrong, A. J., Morris, M. J., Milowsky, M. I., et al. (2024) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-24-0803 · Cited by 11 · see citing works
From Immune Dysregulations to Therapeutic Perspectives in Myelodysplastic Syndromes: A Review
Comont, T., Treiner, E., & Vergez, F. (2021) · Diagnostics · doi:10.3390/diagnostics11111982 · Cited by 10 · see citing works
“Interestingly, TET2 mutant CHIP is more highly associated with elevated IL-6, while DNMT3A mutant CHIP is more highly associated with elevated TNF-α or IFN-γ [96,97].”
BackgroundInfluentialAdvances in understanding the molecular basis of clonal hematopoiesis
Alagpulinsa, D. A., Toribio, M. P., Alhallak, I., & Reis, R. J. S. (2022) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2022.03.002 · Cited by 10 · see citing works
Inflammatory signaling in the pathogenesis of acute myeloid leukemia
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“59 Janus kinase 2 ( JAK2 ) is a non ‐ receptor tyrosine kinase involved in the signal transduction of various cytokines, including interferons and interleukins.”
Cheng, B., Rong, A., Li, W., Bi, X., & Qiu, X. (2022) · Mediators of Inflammation · doi:10.1155/2022/4862763 · Cited by 9 · see citing works
“A sequencing analysis of peripheral blood mononuclear cell DNA from ulcerative colitis patients suggested that DNMT3a was involved in the regulation of UC [51], which has not been identified in UC patients or models.”
BackgroundDecoding Clonal Hematopoiesis: Emerging Themes and Novel Mechanistic Insights
Pendse, S., & Loeffler, D. (2024) · Cancers · doi:10.3390/cancers16152634 · Cited by 8 · see citing works
“Elevated levels of the classical pro-inflammatory factors of IFN-γ , IL-1 β , IL-6, and TNF-α have been repeatedly reported in both mouse models [91] and individuals with CH [142], but additional less well-studied factors such as Oncostatin M are involved, too [90].”
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Clonal Hematopoiesis: Origins and determinants of evolution
Mendez, L., & Patnaik, M. M. (2023) · Leukemia Research · doi:10.1016/j.leukres.2023.107076 · Cited by 8 · see citing works
Clonal Hematopoiesis in Chronic Thromboembolic Pulmonary Hypertension
Momoi, M., Katsumata, Y., Kunimoto, H., Inami, T., Miya, F., Anzai, A., Goto, S., Miura, A., Shinya, Y., Hiraide, T., et al. (2024) · Journal of the American Heart Association · doi:10.1161/jaha.124.035498 · Cited by 7 · see citing works
Turning the clock forward: Inflammation accelerates the aging of hematopoietic stem cells
Burns, S. S., & Kapur, R. (2022) · Cell stem cell · doi:10.1016/j.stem.2022.07.002 · Cited by 7 · see citing works
Park, J., An, H., Lim, J., Park, I. S., Kim, M., Kim, J. H., Kim, S. W., Koh, Y. I., Lee, E. Y., & Cheon, J. H. (2023) · Arthritis Research & Therapy · doi:10.1186/s13075-023-03014-w · Cited by 7 · see citing works
“Subpopulations of CHIP with DNMT3A mutations were significantly associated with higher serum interferon-gamma levels [9].”
BackgroundClonality in haematopoietic stem cell ageing
Terradas-Terradas, M., Robertson, N., Chandra, T., & Kirschner, K. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111279 · Cited by 8 · see citing works
Clonal hematopoiesis of indeterminate potential and risk of autoimmune thyroid disease
Zhang, X. J., Wang, Y., Xue, H., Zhao, Y., Liu, M.-C., Wei, H., & Liu, Q. (2025) · BMC Medicine · doi:10.1186/s12916-025-04077-z · Cited by 6 · see citing works
Clonal hematopoiesis: Molecular basis and clinical relevance
Kunimoto, H., & Nakajima, H. (2020) · Leukemia Research · doi:10.1016/j.leukres.2020.106457 · Cited by 6 · see citing works
Molecular Studies for the Early Detection of Philadelphia-Negative Myeloproliferative Neoplasms
Stuckey, R., Bilbao, C., Segura-Díaz, A., & Gómez‐Casares, M. T. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241612700 · Cited by 6 · see citing works
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Inflammation in Myeloid Malignancies: From Bench to Bedside
Soyfer, E. M., & Fleischman, A. G. (2021) · Journal of Immunotherapy and Precision Oncology · doi:10.36401/jipo-21-3 · Cited by 6 · see citing works
“A cohort of patients with ulcerative colitis was found to have an increased rate of CHIP with DNMT3A and PPM1D mutations.([33]) In addition, inflammation as a result of infection may also impact the development of myeloid malignancies, as there is an increased risk of myeloid malignancies in those with community acqui…”
BackgroundTarget practice: Opportunities for therapeutic intervention in CHIP and CCUS
Mohammad, A., Mascarenhas, J. O., Marcellino, B. K., & Nathan, D. I. (2025) · Blood Reviews · doi:10.1016/j.blre.2025.101323 · Cited by 5 · see citing works
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Hoff, F. W., Trikha, R., Groarke, E. M., & Patel, B. A. (2026) · British Journal of Haematology · doi:10.1111/bjh.70302 · Cited by 5 · see citing works
“36,37 Because much of the symptom burden is associated with systemic inflammation, front-line therapeutic strategies for VEXAS syndrome are aimed to suppress the (auto)inflammatory pathways or cytokines.”
Ottesen, J. T., & Andersen, M. (2023) · Cancers · doi:10.3390/cancers15194806 · Cited by 5 · see citing works
“CHIP is known to be associated with increased morbidity, such as coronary heart disease [21], chronic liver disease [22], chronic kidney disease [12,23], hematologic cancers [3,24], and potentially ulcerative colitis [25] and solid tumors [26].”
BackgroundSun, X., Liu, Y., Liu, Y., Wang, H., Liu, B., & Shi, L. (2023) · Frontiers in Pediatrics · doi:10.3389/fped.2023.1088535 · Cited by 5 · see citing works
“The maturation of erythrocytes may be impacted by the effects of inflammatory cytokines on the pace of bone marrow hematopoiesis, erythropoietin production, and iron metabolism processes (40, 41).”
BackgroundDiagnostic Challenge and Clinical Dilemma: The Long Reach of Clonal Hematopoiesis
Osman, A. E. G., & Patel, J. L. (2021) · Clinical Chemistry · doi:10.1093/clinchem/hvab105 · Cited by 4 · see citing works
- Authors
- Zhang, C. R. C., Nix, D., Gregory, M., Ciorba, M. A., Ostrander, E. L., Newberry, R. D., Spencer, D. H., & Challen, G. A.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Challen, Grant A.
- ORCID
- Venue
- Experimental Hematology
- Publisher
- Elsevier BV
- Published
- 2019-12
- Volume
- 80
- Pages
- 36-41.e3
- ISSN
- 0301-472X (ISSN-L)
- PMC
- PMC7031927
- OpenAlex
- W2993117431
- Cited by
- 137
- References
- 17
- Citations by year
- 2026: 12 · 2025: 21 · 2024: 18 · 2023: 22 · 2022: 27 · 2021: 21 · 2020: 16
- FWCI
- 11.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Experimental Hematology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Golfers Against Cancer (F31DK114951)
- Leukemia and Lymphoma Society
- National Institutes of Health (P30 DK052574)
- Center for Outcomes Research and Evaluation, Yale School of Medicine
- Digestive Diseases Research Core Center, University of Chicago
- Manitoba Arts Council
- 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 of indeterminate potential, ulcerative colitis, inflammatory cytokines, DNMT3A mutation, PPM1D mutation, interferon-gamma, somatic mutations, clonal evolution, hematopoietic stem cells, chronic inflammation, myeloid neoplasms
- MeSH terms
- Protein Phosphatase 2C, DNA Methyltransferase 3A, Aged, Aged, 80 and over, Clone Cells, Colitis, Ulcerative, DNA (Cytosine-5-)-Methyltransferases, Female, Hematopoiesis, Humans, Interferon-gamma, Male, Middle Aged, Mutation, Precancerous Conditions, Tumor Necrosis Factor-alpha
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