TY  - JOUR
AU  - McLoughlin, Matthew A
AU  - Cheloor Kovilakam, Sruthi
AU  - Dunn, William G
AU  - Gu, Muxin
AU  - Tobin, Jake
AU  - Pershad, Yash
AU  - Williams, Nicholas
AU  - Leongamornlert, Daniel
AU  - Dawson, Kevin
AU  - Bond, Laura
AU  - Marando, Ludovica
AU  - Wen, Sean
AU  - Wilson, Rachael
AU  - Valenzano, Giampiero
AU  - Symeonidou, Vasiliki
AU  - Rak, Justyna
AU  - Damaskou, Aristi
AU  - Gozdecka, Malgorzata
AU  - Liu, Xiaoxuan
AU  - Barcena, Clea
AU  - Nomdedeu, Josep
AU  - Costeas, Paul
AU  - Dimitriou, Ioannis D
AU  - Fiorillo, Edoardo
AU  - Orrù, Valeria
AU  - de Almeida, Jose Guilherme
AU  - McKerrell, Thomas
AU  - Cullen, Matthew
AU  - Mohorianu, Irina
AU  - Foukaneli, Theodora
AU  - Warren, Alan J
AU  - Wong, Chi
AU  - Follows, George
AU  - Godfrey, Anna L
AU  - Gudgin, Emma
AU  - Cucca, Francesco
AU  - McKinney, Eoin
AU  - Baxter, E Joanna
AU  - Gerstung, Moritz
AU  - Mitchell, Jonathan
AU  - Wiseman, Daniel
AU  - Bick, Alexander G
AU  - Fabre, Margarete
AU  - Quiros, Pedro M
AU  - Nangalia, Jyoti
AU  - Kar, Siddhartha
AU  - Vassiliou, George S
TI  - Telomere attrition becomes an instrument for clonal selection in aging hematopoiesis and leukemogenesis.
JO  - Nature genetics
VL  - nn
SN  - 1061-4036
CY  - London
PB  - Macmillan Publishers Limited, part of Springer Nature
M1  - DKFZ-2025-01800
SP  - nn
PY  - 2025
N1  - epub
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:40877435
DO  - DOI:10.1038/s41588-025-02296-x
UR  - https://inrepo02.dkfz.de/record/304246
ER  -