Journal article
Microbial metabolite drives ageing-related clonal haematopoiesis via ALPK1
- Abstract:
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Clonal haematopoiesis of indeterminate potential (CHIP) involves the gradual expansion of mutant pre-leukaemic haematopoietic cells, which increases with age and confers a risk for multiple diseases, including leukaemia and immune-related conditions1. Although the absolute risk of leukaemic transformation in individuals with CHIP is very low, the strongest predictor of progression is the accumulation of mutant haematopoietic cells2. Despite the known associations between CHIP and increased all-cause mortality, our understanding of environmental and regulatory factors that underlie this process during ageing remains rudimentary. Here we show that intestinal alterations, which can occur with age, lead to systemic dissemination of a microbial metabolite that promotes pre-leukaemic cell expansion. Specifically, ADP-d-glycero-β-d-manno-heptose (ADP-heptose), a biosynthetic bi-product specific to Gram-negative bacteria3,4,5, is uniquely found in the circulation of older individuals and favours the expansion of pre-leukaemic cells. ADP-heptose is also associated with increased inflammation and cardiovascular risk in CHIP. Mechanistically, ADP-heptose binds to its receptor, ALPK1, triggering transcriptional reprogramming and NF-κB activation that endows pre-leukaemic cells with a competitive advantage due to excessive clonal proliferation. Collectively, we identify that the accumulation of ADP-heptose represents a direct link between ageing and expansion of rare pre-leukaemic cells, suggesting that the ADP-heptose–ALPK1 axis is a promising therapeutic target to prevent progression of CHIP to overt leukaemia and immune-related conditions.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Files:
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(Preview, Version of record, pdf, 13.7MB, Terms of use)
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- Publisher copy:
- 10.1038/s41586-025-08938-8
Authors
- Funder identifier:
- https://ror.org/03x94j517
- Grant:
- MC_UU_00029/8
- MR/R002258/1
- Funder identifier:
- https://ror.org/0187kwz08
- Publisher:
- Springer Nature
- Journal:
- Nature More from this journal
- Volume:
- 642
- Issue:
- 8066
- Pages:
- 201-211
- Publication date:
- 2025-04-23
- Acceptance date:
- 2025-03-26
- DOI:
- EISSN:
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1476-4687
- ISSN:
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0028-0836
- Pmid:
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40269158
- Language:
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English
- Keywords:
- Pubs id:
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2120171
- Local pid:
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pubs:2120171
- Deposit date:
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2025-05-02
- ARK identifier:
Terms of use
- Copyright holder:
- Agarwal et al.
- Copyright date:
- 2025
- Rights statement:
- Copyright © 2025, The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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