Journal Article

DKFZ-2025-01800

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Telomere attrition becomes an instrument for clonal selection in aging hematopoiesis and leukemogenesis.

McLoughlin, M. A. ; Cheloor Kovilakam, S. ; Dunn, W. G. ; Gu, M. ; Tobin, J. ; Pershad, Y. ; Williams, N. ; Leongamornlert, D. ; Dawson, K. ; Bond, L. ; Marando, L. ; Wen, S. ; Wilson, R. ; Valenzano, G. ; Symeonidou, V. ; Rak, J. ; Damaskou, A. ; Gozdecka, M. ; Liu, X. ; Barcena, C. ; Nomdedeu, J. ; Costeas, P. ; Dimitriou, I. D. ; Fiorillo, E. ; Orrù, V. ; de Almeida, J. G. ; McKerrell, T. ; Cullen, M. ; Mohorianu, I. ; Foukaneli, T. ; Warren, A. J. ; Wong, C. ; Follows, G. ; Godfrey, A. L. ; Gudgin, E. ; Cucca, F. ; McKinney, E. ; Baxter, E. J. ; Gerstung, M.DKFZ* ; Mitchell, J. ; Wiseman, D. ; Bick, A. G. ; Fabre, M. ; Quiros, P. M. ; Nangalia, J. ; Kar, S. ; Vassiliou, G. S.

2025
Macmillan Publishers Limited, part of Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s41588-025-02296-x

Abstract: 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.

Note: 2025 Sep;57(9):2215-2225

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Contributing Institute(s):

1. Künstl. Intelligenz in der Onkologie (B450)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 30 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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