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Inflammatory bowel disease–induced inflammation augments clonal hematopoiesis of indeterminate potential through Ref-1

Kumar, Ramesh ; Li, Linke ; Urbut, Sarah ; Uddin, Mesbah ; Niroula, Abhishek LU ; Kanumuri, Rahul ; Ramdas, Baskar ; Pasupuleti, Santhosh Kumar ; Palam, Lakshmi Reddy and Wang, Xuepeng , et al. (2026) In Blood
Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by age-related somatic mutations in hematopoietic stem and progenitor cells (HSC/Ps) and is correlated with an increased risk of myeloid malignancies, elevated inflammatory pathways in circulating myeloid cells, higher all-cause mortality, chronic kidney disease, and cardiovascular disease. The pathophysiology of inflammatory bowel disease (IBD) is intrinsically linked to heightened inflammation. Nevertheless, the presence of CHIP in IBD and its role in the pathophysiology of IBD remains poorly elucidated. In the UK Biobank, CHIP was associated with an increased incidence of IBD. Females with CHIP had a 1.33-fold higher risk, which was further validated in the All... (More)

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by age-related somatic mutations in hematopoietic stem and progenitor cells (HSC/Ps) and is correlated with an increased risk of myeloid malignancies, elevated inflammatory pathways in circulating myeloid cells, higher all-cause mortality, chronic kidney disease, and cardiovascular disease. The pathophysiology of inflammatory bowel disease (IBD) is intrinsically linked to heightened inflammation. Nevertheless, the presence of CHIP in IBD and its role in the pathophysiology of IBD remains poorly elucidated. In the UK Biobank, CHIP was associated with an increased incidence of IBD. Females with CHIP had a 1.33-fold higher risk, which was further validated in the All of Us database (ßodds ratio, 1.29). For Crohn's disease, DNA methyltransferase 3A (DNMT3A) mutations conferred a 1.81-fold increased incidence in females compared with non-DNMT3A carriers, which rose to 2.09 for large clones (variant allele fraction of ≥10%). In contrast, for ulcerative colitis, TET2 large clones were significantly associated, and only among individuals aged <45 years. These associations were further identified using 2-sample Mendelian randomization. In a mouse model of CHIP-IBD, HSC/Ps with Dnmt3a mutation demonstrated significantly worse pathophysiology compared with controls, due, in part, to heightened expression of apurinic/apyrimidinic endonuclease 1 (APE1) in the bone marrow and colon. Treatment with the APE1/redox factor 1 inhibitor APX3330 ameliorated CHIP-IBD driven by the Dnmt3a mutation.

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Contribution to journal
publication status
in press
subject
in
Blood
publisher
American Society of Hematology
external identifiers
  • pmid:41746260
  • scopus:105035328358
ISSN
0006-4971
DOI
10.1182/blood.2025032339
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2026 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. This is an open access article under the CC BY-NC-ND license. http://creativecommons.org/licenses/by-nc-nd/4.0/
id
72a103ef-cef0-4087-837f-5fc8ec850aeb
date added to LUP
2026-05-27 15:25:03
date last changed
2026-05-29 13:08:37
@article{72a103ef-cef0-4087-837f-5fc8ec850aeb,
  abstract     = {{<p>Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by age-related somatic mutations in hematopoietic stem and progenitor cells (HSC/Ps) and is correlated with an increased risk of myeloid malignancies, elevated inflammatory pathways in circulating myeloid cells, higher all-cause mortality, chronic kidney disease, and cardiovascular disease. The pathophysiology of inflammatory bowel disease (IBD) is intrinsically linked to heightened inflammation. Nevertheless, the presence of CHIP in IBD and its role in the pathophysiology of IBD remains poorly elucidated. In the UK Biobank, CHIP was associated with an increased incidence of IBD. Females with CHIP had a 1.33-fold higher risk, which was further validated in the All of Us database (ß<sub>odds ratio</sub>, 1.29). For Crohn's disease, DNA methyltransferase 3A (DNMT3A) mutations conferred a 1.81-fold increased incidence in females compared with non-DNMT3A carriers, which rose to 2.09 for large clones (variant allele fraction of ≥10%). In contrast, for ulcerative colitis, TET2 large clones were significantly associated, and only among individuals aged &lt;45 years. These associations were further identified using 2-sample Mendelian randomization. In a mouse model of CHIP-IBD, HSC/Ps with Dnmt3a mutation demonstrated significantly worse pathophysiology compared with controls, due, in part, to heightened expression of apurinic/apyrimidinic endonuclease 1 (APE1) in the bone marrow and colon. Treatment with the APE1/redox factor 1 inhibitor APX3330 ameliorated CHIP-IBD driven by the Dnmt3a mutation.</p>}},
  author       = {{Kumar, Ramesh and Li, Linke and Urbut, Sarah and Uddin, Mesbah and Niroula, Abhishek and Kanumuri, Rahul and Ramdas, Baskar and Pasupuleti, Santhosh Kumar and Palam, Lakshmi Reddy and Wang, Xuepeng and Ram Padam, Kanaka Sai and Kelley, Mark and Natarajan, Pradeep and Yu, Zhi and Kapur, Reuben}},
  issn         = {{0006-4971}},
  language     = {{eng}},
  publisher    = {{American Society of Hematology}},
  series       = {{Blood}},
  title        = {{Inflammatory bowel disease–induced inflammation augments clonal hematopoiesis of indeterminate potential through Ref-1}},
  url          = {{http://dx.doi.org/10.1182/blood.2025032339}},
  doi          = {{10.1182/blood.2025032339}},
  year         = {{2026}},
}