Language

English

Publication Date

4-15-2025

Journal

Journal of Clinical Investigation

DOI

10.1172/JCI181659

PMID

40179146

PMCID

PMC11996883

PubMedCentral® Posted Date

4-3-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Telomere biology disorders (TBDs) are genetic diseases caused by defective telomere maintenance. TBD patients often develop bone marrow failure and have an increased risk of myeloid neoplasms. To better understand the factors underlying hematopoietic outcomes in TBD, we comprehensively evaluated acquired genetic alterations in hematopoietic cells from 166 pediatric and adult TBD patients. Of these patients, 47.6% (28.8% of children, 56.1% of adults) had clonal hematopoiesis. Recurrent somatic alterations involved telomere maintenance genes (7.6%), spliceosome genes (10.4%, mainly U2AF1 p.S34), and chromosomal alterations (20.2%), including 1q gain (5.9%). Somatic variants affecting the DNA damage response (DDR) were identified in 21.5% of patients, including 20 presumed loss-of-function variants in ataxia-telangiectasia mutated (ATM). Using multimodal approaches, including single-cell sequencing, assays of ATM activation, telomere dysfunction-induced foci analysis, and cell-growth assays, we demonstrate telomere dysfunction-induced activation of the ATM-dependent DDR pathway with increased senescence and apoptosis in TBD patient cells. Pharmacologic ATM inhibition, modeling the effects of somatic ATM variants, selectively improved TBD cell fitness by allowing cells to bypass DDR-mediated senescence without detectably inducing chromosomal instability. Our results indicate that ATM-dependent DDR induced by telomere dysfunction is a key contributor to TBD pathogenesis and suggest dampening hyperactive ATM-dependent DDR as a potential therapeutic intervention.

Keywords

Humans, Ataxia Telangiectasia Mutated Proteins, Telomere, DNA Damage, Clonal Hematopoiesis, Adult, Male, Female, Child, Adolescent, Child, Preschool, Cell Proliferation, Middle Aged, Hematology, Oncology, Clonal selection, Hematopoietic stem cells, Telomeres

Published Open-Access

yes

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