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Recurrent somatic alterations involved telomere maintenance genes (7.6%), spliceosome genes (10.4%, mainly\n                    <jats:italic>U2AF1<\/jats:italic>\n                    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 (\n                    <jats:italic>ATM<\/jats:italic>\n                    ). Using multimodal approaches, including single-cell sequencing, assays of ATM activation, telomere dysfunction-induced foci analysis, and cell-growth assays, we demonstrate telomere dysfunction\u2013induced activation of the ATM-dependent DDR pathway with increased senescence and apoptosis in TBD patient cells. Pharmacologic ATM inhibition, modeling the effects of somatic\n                    <jats:italic>ATM<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1172\/jci181659","type":"journal-article","created":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T17:40:45Z","timestamp":1743702045000},"source":"Crossref","is-referenced-by-count":16,"title":["ATM-dependent DNA damage response constrains cell growth and drives clonal hematopoiesis in telomere biology disorders"],"prefix":"10.1172","volume":"135","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5868-1986","authenticated-orcid":true,"given":"Christopher M.","family":"Sande","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA."},{"name":"Department of Laboratories, Seattle Children\u2019s Hospital, Seattle, Washington, 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