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<p>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 <i>PPM1D</i> and the <i>TERT</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月28日

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  • 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

摘要

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.