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.

剪接因子基因（splicing factor genes）的突变可驱动克隆性造血（clonal hematopoiesis, CH）与髓系肿瘤，但该现象的机制基础迄今仍未阐明。本研究揭示了端粒维持在这一过程中发挥重要作用的相关证据。
首先，通过对450837名英国生物样本库（UK Biobank）参与者的研究，我们发现：与多数在遗传预测端粒长度更长的个体中更为高发的克隆性造血亚型不同，由剪接因子基因SRSF2、SF3B1或DNA损伤应答基因（DNA damage response gene）PPM1D突变驱动的克隆性造血，在遗传预测端粒长度更短的个体中更为常见。
我们进一步证实，端粒耗竭会在高龄时期成为克隆选择的驱动因素，而剪接因子基因突变可通过阻止或减缓端粒耗竭，使造血干细胞（hematopoietic stem cells, HSCs）免于发生临界端粒缩短。
本研究揭示了端粒维持对造血过程及克隆选择的终生影响，并明确了突变型剪接因子基因驱动白血病发生的共同机制。后续针对该现象分子基础的研究，可为剪接因子突变型癌症开辟全新的治疗途径。