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

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

doi:10.1038/s41588-025-02296-x

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

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 BarcenaJosep 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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	2215-2225
Number of pages	11
Journal	Nature Genetics
Volume	57
Issue number	9
DOIs	https://doi.org/10.1038/s41588-025-02296-x
Publication status	Published - Sept 2025

Keywords

Humans
Telomere/genetics
Clonal Hematopoiesis/genetics
Mutation
Aging/genetics
Male
Aged
Telomerase/genetics
Female
Middle Aged
Hematopoiesis/genetics
RNA Splicing Factors/genetics
Telomere Shortening/genetics
Leukemia/genetics
Adult
Carcinogenesis/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41588-025-02296-x

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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., ... Vassiliou, G. S. (2025). Telomere attrition becomes an instrument for clonal selection in aging hematopoiesis and leukemogenesis. Nature Genetics, 57(9), 2215-2225. https://doi.org/10.1038/s41588-025-02296-x

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title = "Telomere attrition becomes an instrument for clonal selection in aging hematopoiesis and leukemogenesis",

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.",

keywords = "Humans, Telomere/genetics, Clonal Hematopoiesis/genetics, Mutation, Aging/genetics, Male, Aged, Telomerase/genetics, Female, Middle Aged, Hematopoiesis/genetics, RNA Splicing Factors/genetics, Telomere Shortening/genetics, Leukemia/genetics, Adult, Carcinogenesis/genetics",

author = "McLoughlin, \{Matthew A\} and \{Cheloor Kovilakam\}, Sruthi and Dunn, \{William G\} and Muxin Gu and Jake Tobin and Yash Pershad and Nicholas Williams and Daniel Leongamornlert and Kevin Dawson and Laura Bond and Ludovica Marando and Sean Wen and Rachael Wilson and Giampiero Valenzano and Vasiliki Symeonidou and Justyna Rak and Aristi Damaskou and Malgorzata Gozdecka and Xiaoxuan Liu and Clea Barcena and Josep Nomdedeu and Paul Costeas and Dimitriou, \{Ioannis D\} and Edoardo Fiorillo and Valeria Orr{\`u} and \{de Almeida\}, \{Jose Guilherme\} and Thomas McKerrell and Matthew Cullen and Irina Mohorianu and Theodora Foukaneli and Warren, \{Alan J\} and Chi Wong and George Follows and Godfrey, \{Anna L\} and Emma Gudgin and Francesco Cucca and Eoin McKinney and Baxter, \{E Joanna\} and Moritz Gerstung and Jonathan Mitchell and Daniel Wiseman and Bick, \{Alexander G\} and Margarete Fabre and Quiros, \{Pedro M\} and Jyoti Nangalia and Siddhartha Kar and Vassiliou, \{George S\}",

note = "{\textcopyright} 2025. The Author(s).",

year = "2025",

month = sep,

doi = "10.1038/s41588-025-02296-x",

language = "English",

volume = "57",

pages = "2215--2225",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "9",

}

McLoughlin, MA, Cheloor Kovilakam, S, Dunn, WG, 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, ID, Fiorillo, E, Orrù, V, de Almeida, JG, McKerrell, T, Cullen, M, Mohorianu, I, Foukaneli, T, Warren, AJ, Wong, C, Follows, G, Godfrey, AL, Gudgin, E, Cucca, F, McKinney, E, Baxter, EJ, Gerstung, M, Mitchell, J, Wiseman, D, Bick, AG, Fabre, M, Quiros, PM, Nangalia, J, Kar, S & Vassiliou, GS 2025, 'Telomere attrition becomes an instrument for clonal selection in aging hematopoiesis and leukemogenesis', Nature Genetics, vol. 57, no. 9, pp. 2215-2225. https://doi.org/10.1038/s41588-025-02296-x

TY - JOUR

T1 - Telomere attrition becomes an instrument for clonal selection in aging hematopoiesis and leukemogenesis

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

PY - 2025/9

Y1 - 2025/9

N2 - 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.

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.

KW - Humans

KW - Telomere/genetics

KW - Clonal Hematopoiesis/genetics

KW - Mutation

KW - Aging/genetics

KW - Male

KW - Aged

KW - Telomerase/genetics

KW - Female

KW - Middle Aged

KW - Hematopoiesis/genetics

KW - RNA Splicing Factors/genetics

KW - Telomere Shortening/genetics

KW - Leukemia/genetics

KW - Adult

KW - Carcinogenesis/genetics

U2 - 10.1038/s41588-025-02296-x

DO - 10.1038/s41588-025-02296-x

M3 - Article

C2 - 40877435

SN - 1061-4036

VL - 57

SP - 2215

EP - 2225

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

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

Abstract

Keywords

UN SDGs

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