Authors
Matthew A McLoughlin, Sruthi Cheloor Kovilakam, William G Dunn, Muxin Gu, Jake Tobin, Yash Pershad, Nicholas Williams, Daniel Leongamornlert, Kevin Dawson, Laura Bond, Ludovica Marando, Sean Wen, Rachael Wilson, Giampiero Valenzano, Vasiliki Symeonidou, Justyna Rak, Aristi Damaskou, Malgorzata Gozdecka, Xiaoxuan Liu, Clea Barcena, Josep Nomdedeu, Paul Costeas, Ioannis D Dimitriou, Edoardo Fiorillo, Valeria Orrù, Jose Guilherme de Almeida, Thomas McKerrell, Matthew Cullen, Irina Mohorianu, Theodora Foukaneli, Alan J Warren, Chi Wong, George Follows, Anna L Godfrey, Emma Gudgin, Francesco Cucca, Eoin McKinney, E Joanna Baxter, Moritz Gerstung, Jonathan Mitchell, Daniel Wiseman, Alexander G Bick, Margarete Fabre, Pedro M Quiros, Jyoti Nangalia, Siddhartha Kar, George S Vassiliou
Published in
Nature genetics. Aug 28, 2025. Epub Aug 28, 2025.
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.
PMID:
40877435
Bibliographic data and abstract were imported from PubMed on 29 Aug 2025.
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