Telomere attrition becomes an instrument for clonal selection in aging hematopoiesis and leukemogenesis
The mechanisms through which mutations in splicing factor genes drive clonal hematopoiesis (CH) and myeloid malignancies, and their close association with advanced age, remain poorly understood. Here we show that telomere maintenance plays an important role in this phenomenon. First, by studying 454,098 UK Biobank participants, we find that, unlike most CH subtypes, splicing-factor-mutant CH is more common in those with shorter genetically predicted telomeres, as is CH with mutations in PPM1D and the TERT gene promoter. We go on to show that telomere attrition becomes an instrument for clonal selection in advanced age, with splicing factor mutations 'rescuing' HSCs from critical telomere shortening. Our findings expose the lifelong influence of telomere maintenance on hematopoiesis and identify a potential shared mechanism through which different splicing factor mutations drive leukemogenesis. Understanding the mechanistic basis of these observations can open new therapeutic avenues against splicing-factor-mutant CH and hematological or other cancers.
Authors
- Daniel Leongamornlert (ORCID: https://orcid.org/0000-0002-3486-3168)
- Moritz Gerstung (ORCID: https://orcid.org/0000-0001-6709-963X)
- Pedro M. Quirós (ORCID: https://orcid.org/0000-0002-7793-6291)
- Malgorzata Gozdecka
- George Follows (ORCID: https://orcid.org/0000-0002-8489-0762)
- Alexander G. Bick (ORCID: https://orcid.org/0000-0001-5824-9595)
- Daniel H. Wiseman (ORCID: https://orcid.org/0000-0003-0715-1402)
- Theodora Foukaneli (ORCID: https://orcid.org/0000-0003-4119-8378)
- George S. Vassiliou (ORCID: https://orcid.org/0000-0003-4337-8022)
- Ludovica Marando (ORCID: https://orcid.org/0000-0002-6154-850X)
- Anna L. Godfrey (ORCID: https://orcid.org/0000-0003-1955-9499)
- Eoin McKinney (ORCID: https://orcid.org/0000-0003-3516-3072)
- Alan J. Warren (ORCID: https://orcid.org/0000-0001-9277-4553)
- Josep F. Nomdedeu (ORCID: https://orcid.org/0000-0003-3399-346X)
- Paul Costeas (ORCID: https://orcid.org/0000-0002-7257-4746)
- Aristi Damaskou
- Xiaoxuan Liu (ORCID: https://orcid.org/0000-0002-1286-0038)
- Rachael Wilson (ORCID: https://orcid.org/0000-0001-5129-7295)
- Clea Bárcena (ORCID: https://orcid.org/0000-0002-7452-2536)
- Justyna Rak (ORCID: https://orcid.org/0000-0002-9398-4947)
- Yash Pershad (ORCID: https://orcid.org/0000-0002-2282-1403)
- Francesco Cucca (ORCID: https://orcid.org/0000-0002-7414-1995)
- William G. Dunn (ORCID: https://orcid.org/0000-0001-7246-5198)
- E. Joanna Baxter (ORCID: https://orcid.org/0000-0002-5946-5238)
- Irina Mohorianu (ORCID: https://orcid.org/0000-0003-4863-761X)
- Margarete A. Fabre (ORCID: https://orcid.org/0000-0001-7794-610X)
- Muxin Gu (ORCID: https://orcid.org/0000-0003-4376-795X)
- Valeria Orrù (ORCID: https://orcid.org/0000-0002-6047-4625)
- Emma Gudgin
- Chi Kuen Wong (ORCID: https://orcid.org/0000-0001-9792-4792)
- Nicholas Williams (ORCID: https://orcid.org/0000-0003-3989-9167)
- Ioannis D. Dimitriou (ORCID: https://orcid.org/0000-0001-5778-8896)
- Siddhartha Kar (ORCID: https://orcid.org/0000-0002-2314-1426)
- Vasiliki Symeonidou (ORCID: https://orcid.org/0000-0003-1595-1135)
- José Guilherme de Almeida (ORCID: https://orcid.org/0000-0002-1887-0157)
- Jake Tobin (ORCID: https://orcid.org/0009-0001-2939-0896)
- Jyoti Nangalia (ORCID: https://orcid.org/0000-0001-7122-4608)
- Thomas McKerrell
- Giampiero Valenzano (ORCID: https://orcid.org/0009-0000-4882-4066)
- Sruthi Cheloor Kovilakam
- Sean Wen
- Edoardo Fiorillo (ORCID: https://orcid.org/0000-0002-8690-4988)
- Kevin J. Dawson
- Laura Bond (ORCID: https://orcid.org/0000-0001-6115-655X)
- Jonathan Mitchell (ORCID: https://orcid.org/0000-0003-3792-4058)
- Matthew McLoughlin (ORCID: https://orcid.org/0000-0002-4782-5718)
- Matthew J. Cullen
Institutions
- AstraZeneca (United Kingdom) (GB)
- Champalimaud Foundation (PT)
- Mayo Clinic (US)
- Cyprus Institute (CY)
- Deakin University (AU)
- University of Sassari (IT)
- Universidad de Oviedo (ES)
- German Cancer Research Center (DE)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Heidelberg University (DE)
- University of Cambridge (GB)
- Geelong Hospital (AU)
- Hospital de Sant Pau (ES)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Wellcome Sanger Institute (GB)
- Cancer Research UK Cambridge Center (GB)
- Center for the Study of Childhood and Adolescence (CY)
- Institute of Genetic and Biomedical Research (IT)
- Mayo Clinic in Arizona (US)
- Cancer Research UK Manchester Institute (GB)
- Mayo Clinic in Florida (US)
- National Research Council (IT)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-08-28
- DOI
- https://doi.org/10.1038/s41588-025-02296-x
- Citations
- 8
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 14.16
Funders
- Alexander and Margaret Stewart Trust
- AstraZeneca
- Leukemia and Lymphoma Society
- Wellcome Trust
- UK Research and Innovation
- Cancer Research UK
- National Institute for Health and Care Research
- European Commission
- Rosetrees Trust
- Blood Cancer UK
- National Institutes of Health
- Medical Research Council
- Instituto de Salud Carlos III
- Agencia Estatal de Investigación