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

Mutations in splicing factor genes drive clonal hematopoiesis (CH) and myeloid neoplasia, but the mechanistic basis of this remains unknown. Here, we uncover evidence that telomere maintenance plays an important role in this phenomenon. First, by studying 450,837 UK Biobank participants, we find that unlike most subtypes of CH that are more common in individuals with longer genetically predicted telomeres, CH driven by mutations in the splicing factor genes SRSF2 and SF3B1, or the DNA damage response gene PPM1D, are more common in those with shorter genetically predicted telomeres. We go on to show that telomere attrition becomes an instrument for clonal selection in advanced age, with splicing factor gene mutations rescuing HSCs from critical telomere shortening by preventing or slowing telomere attrition. Our findings expose the lifelong influence of telomere maintenance on hematopoiesis and clonal selection, and identify a shared mechanism through which mutant splicing factor genes drive leukemogenesis. Future studies to understand the molecular basis of this can open new therapeutic avenues against splicing factor-mutant cancers.