A major UK-based study has revealed a new link between ageing, DNA changes and the development of blood cancers. Researchers analysing data from 454,098 UK Biobank participants found that individuals with shorter genetically predicted telomeres are more likely to carry harmful mutations in splicing factor genes. These mutations are closely associated with clonal haematopoiesis (CH) and myeloid malignancies.
Telomeres are protective caps at the ends of chromosomes that naturally shorten with age. While telomere shortening has long been linked to ageing and disease, this new research suggests it may actively drive the selection of harmful mutations. The study found that CH involving splicing factor mutations, unlike most other CH subtypes, is significantly more common in individuals with shorter telomeres. Similar associations were observed for mutations in the PPM1D gene and the TERT gene promoter.
The researchers propose that in later life, telomere attrition creates selective pressure that favours haematopoietic stem cells (HSCs) carrying splicing factor mutations, as these mutations may allow the cells to survive despite critically short telomeres.
The findings highlight the lifelong role of telomere maintenance in blood cell development and suggest that different splicing factor mutations may drive leukaemia through a shared mechanism. Experts believe this discovery could lead to new therapeutic approaches aimed at preventing or treating splicing-factor-mutant CH and related blood cancers.
Helena Bradbury, EMJ
Reference
McLoughlin MA et al. Telomere attrition becomes an instrument for clonal selection in aging hematopoiesis and leukemogenesis. Nat Genet. 2025; doi: 10.1038/s41588-025-02296-x.
