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@ARTICLE{McLoughlin:304246,
author = {M. A. McLoughlin and S. Cheloor Kovilakam and W. G. Dunn
and M. Gu and J. Tobin and Y. Pershad and N. Williams and D.
Leongamornlert and K. Dawson and L. Bond and L. Marando and
S. Wen and R. Wilson and G. Valenzano and V. Symeonidou and
J. Rak and A. Damaskou and M. Gozdecka and X. Liu and C.
Barcena and J. Nomdedeu and P. Costeas and I. D. Dimitriou
and E. Fiorillo and V. Orrù and J. G. de Almeida and T.
McKerrell and M. Cullen and I. Mohorianu and T. Foukaneli
and A. J. Warren and C. Wong and G. Follows and A. L.
Godfrey and E. Gudgin and F. Cucca and E. McKinney and E. J.
Baxter and M. Gerstung$^*$ and J. Mitchell and D. Wiseman
and A. G. Bick and M. Fabre and P. M. Quiros and J. Nangalia
and S. Kar and G. S. Vassiliou},
title = {{T}elomere attrition becomes an instrument for clonal
selection in aging hematopoiesis and leukemogenesis.},
journal = {Nature genetics},
volume = {nn},
issn = {1061-4036},
address = {London},
publisher = {Macmillan Publishers Limited, part of Springer Nature},
reportid = {DKFZ-2025-01800},
pages = {nn},
year = {2025},
note = {epub},
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.},
cin = {B450},
ddc = {570},
cid = {I:(DE-He78)B450-20160331},
pnm = {312 - Funktionelle und strukturelle Genomforschung
(POF4-312)},
pid = {G:(DE-HGF)POF4-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40877435},
doi = {10.1038/s41588-025-02296-x},
url = {https://inrepo02.dkfz.de/record/304246},
}