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Telomere attrition becomes an instrument for clonal selection in aging hematopoiesis and leukemogenesis

McLoughlin, M. A.
; 
Cheloor Kovilakam, S.
; 
Dunn, W. G.
; 
Gu, M.
; 
Tobin, J.
; 
Pershad, Y.
; 
Williams, N.
; 
Leongamornlert, D.
; 
Dawson, K.
; 
Bond, L.
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Abstract
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
McLoughlin, M. A.
Cheloor Kovilakam, S.
Dunn, W. G.
Gu, M.
Tobin, J.
Pershad, Y.
Williams, N.
Leongamornlert, D.
Dawson, K.
Bond, L.
Marando, L.
Wen, S.
Wilson, R.
Valenzano, G.
Symeonidou, V.
Rak, J.
Damaskou, A.
Gozdecka, M.
Liu, X.
Barcena, C.
Nomdedeu, J.
Costeas, P.
Dimitriou, I. D.
Fiorillo, E.
Orrù, V.
de Almeida, J. G.
McKerrell, T.
Cullen, M.
Mohorianu, I.
Foukaneli, T.
Warren, A. J.
Wong, C.
Follows, G.
Godfrey, A. L.
Gudgin, E.
Cucca, F.
McKinney, E.
Baxter, E. J.
Gerstung, M.
Mitchell, J.
Wiseman, D.
Bick, A. G.
Fabre, M.
Quiros, P. M.
Nangalia, J.
Kar, S.
Vassiliou, G. S.
Affiliation
Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge, UK. Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. Wellcome Sanger Institute, Hinxton, Cambridge, UK. Department of Hematology, Mayo Clinic, Rochester, MI, USA. Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. Department of Biochemistry and Molecular Biology, Instituto Universitario de Oncología (IUOPA),Universidad de Oviedo, Oviedo, Spain. Hospital Sant Pau, Barcelona, Spain. Centre for the Study of Haematological Malignancies, Nicosia, Cyprus. Cyprus Cancer Research Institute, Nicosia, Cyprus. Institute for Genetic and Biomedical Research, National Research Council, Lanusei, Italy. Computational Clinical Imaging Group, Champalimaud Foundation, Lisbon, Portugal. Department of Haematology, University Hospital Geelong, Geelong, Victoria, Australia. School of Medicine, Deakin University Geelong, Geelong, Victoria, Australia. Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK. Department of Biomedical Science, University of Sassari, Sassari, Italy. Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK. Division of AI in Oncology, German Cancer Research Centre DKFZ, Heidelberg, Germany. Cancer Research UK, Manchester Institute, Manchester, UK. Department of Oncology, Early Cancer Institute, University of Cambridge, Cambridge, UK. Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. gsv20@cam.ac.uk. Department of Haematology, University of Cambridge, Cambridge, UK. gsv20@cam.ac.uk. Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge, UK. gsv20@cam.ac.uk. Centre for the Study of Haematological Malignancies, Nicosia, Cyprus. gsv20@cam.ac.uk. Cyprus Cancer Research Institute, Nicosia, Cyprus. gsv20@cam.ac.uk.
Description
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2025
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All Paterson Institute for Cancer Research
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McLoughlin MA, Cheloor Kovilakam S, Dunn WG, Gu M, Tobin J, Pershad Y, et al. Telomere attrition becomes an instrument for clonal selection in aging hematopoiesis and leukemogenesis. Nature genetics. 2025 Sep;57(9):2215-25. PubMed PMID: 40877435. Pubmed Central PMCID: PMC12425810 grant from AstraZeneca for research unrelated to that presented here. M.A.F., S.W. and J.M. are employees and stockholders of AstraZeneca. A.J.W. is a consultant for SDS Therapeutics. The other authors declare no competing interests. Epub 2025/08/29. eng.
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https://christie.openrepository.com/handle/10541/628147
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