A groundbreaking study led by Professor George Vassiliou at the Cambridge Stem Cell Institute and University of Cambridge has revealed that age-related telomere shortening plays a key role in the development of clonal haematopoiesis (CH) and blood cancers driven by mutations in RNA splicing genes. The findings, published this week in Nature Genetics, shed light on a long-standing biological mystery and could open the door to new targeted therapies for the prevention and treatment of high-risk blood cancers.
CH, the expansion of mutant blood stem cells over time, is recognized as the precursor to myeloid malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). While mutations in genes like DNMT3A and TET2 explain most cases of CH, cases of CH driven by splicing factor gene mutations (SF3B1, SRSF2, U2AF1) have puzzled researchers as they appear later in life and are strongly associated with blood cancer development.
By analysing data from 454,098 participants in the UK Biobank, the researchers discovered that individuals with shorter genetically predicted telomeres were more likely to develop CH driven by mutations in splicing factor genes, the PPM1D gene and the promoter of the TERT gene. Telomeres, the protective DNA “caps” at the ends of chromosomes, naturally shorten with each cell division, limiting stem cell function. This study found that such mutations appear to “rescue” blood stem cells from this fate, granting them a survival advantage later in life. Unfortunately, in the case of splicing factor genes these “rescued” stem cells can expand, acquire more mutations and progress towards MDS or AML.
Professor Vassiliou, Professor of Haematological Medicine and Honorary Consultant Haematologist at Cambridge University Hospitals explained: “Our results suggest that telomere attrition acts as an engine of clonal selection in ageing blood. Mutations in splicing factor genes seem to prevent or compensate for critical telomere shortening, which explains both their age-related emergence and their strong link to leukaemia.”
The study also confirmed that blood stem cells with splicing factor gene mutations maintained or even elongated their telomeres, unlike most other types of CH that are associated with decreasing telomere length as they expand. This insight highlights a shared evolutionary mechanism by which diverse mutations may drive pre-leukaemia.
Dr William Dunn, PhD Student and joint-first author of the study, explained: “Using a state-of-the-art approach we were able to show that, within the same person, cells with splicing factor gene mutations had longer telomeres than other cells, giving them a growth advantage over neighbouring cells struggling with shortened telomeres”.
By identifying telomere biology as a critical target for splicing factor mutations, the research points to new therapeutic possibilities. Drugs that modulate telomere maintenance or target the specific advantages conferred by these mutations could transform prevention and treatment strategies for many patients with age-related blood cancers.
Dr Matthew McLoughlin, Research Associate at CSCI and joint-first author of the study said: “This work underscores the lifelong influence of telomere dynamics on blood health and cancer risk. Understanding this relationship gives us a powerful new angle to treat different forms of leukaemia or intercept them before they develop.”