Journal article
ATM-dependent DNA damage response constrains cell growth and drives clonal hematopoiesis in telomere biology disorders
The Journal of clinical investigation, v 135(8), pp 1-22
30 Apr 2025
PMID: 40179146
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
A multicenter study of 166 patients with telomere biology disorders identified frequent somatic mutations in patients’ hematopoietic cells, uncovering a previously unknown mechanism of somatic rescue.
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Details
- Title
- ATM-dependent DNA damage response constrains cell growth and drives clonal hematopoiesis in telomere biology disorders
- Creators
- Christopher M. Sande - University of WashingtonStone Chen - Hospital of the University of PennsylvaniaDana V. Mitchell - Children's Hospital of PhiladelphiaPing Lin - Children's Hospital of PhiladelphiaDiana M. Abraham - Hospital of the University of PennsylvaniaJessie Minxuan Cheng - Hospital of the University of PennsylvaniaTalia Gebhard - Children's Hospital of PhiladelphiaRujul J. Deolikar - Hospital of the University of PennsylvaniaColby Freeman - Hospital of the University of PennsylvaniaMary Zhou - Hospital of the University of PennsylvaniaSushant Kumar - Hospital of the University of PennsylvaniaMichael Bowman - University of PennsylvaniaRobert L. Bowman - University of PennsylvaniaShannon Zheng - Hospital of the University of PennsylvaniaBolormaa Munkhbileg - Children's Hospital of PhiladelphiaQijun Chen - Hospital of the University of PennsylvaniaNatasha L. Stanley - Children's Hospital of PhiladelphiaKathy Guo - Hospital of the University of PennsylvaniaAjibike Lapite - Baylor College of MedicineRyan Hausler - Hospital of the University of PennsylvaniaDeanne M. Taylor - Children's Hospital of PhiladelphiaJames Corines - Hospital of the University of PennsylvaniaJennifer J.D. Morrissette - Hospital of the University of PennsylvaniaDavid B. Lieberman - Hospital of the University of PennsylvaniaGuang Yang - Hospital of the University of PennsylvaniaOlga Shestova - Hospital of the University of PennsylvaniaSaar Gill - Hospital of the University of PennsylvaniaJiayin Zheng - Children's Hospital of PhiladelphiaKelcy Smith-Simmer - University of Wisconsin–MadisonLauren G. Banaszak - University of Wisconsin–MadisonKyle N. Shoger - University of Wisconsin–MadisonErica F. Reinig - University of Wisconsin–MadisonMadilynn Peterson - University of Wisconsin–MadisonPeter Nicholas - Children's Hospital of PhiladelphiaAmanda J. Walne - Queen Mary University of LondonInderjeet Dokal - Queen Mary University of LondonJustin P. Rosenheck - The Ohio State UniversityKarolyn A. Oetjen - Washington University in St. LouisDaniel C. Link - Washington University in St. LouisAndrew E. Gelman - Washington University in St. LouisChristopher R. Reilly - Dana-Farber Cancer InstituteRitika Dutta - Dana-Farber Cancer InstituteR. Coleman Lindsley - Dana-Farber Cancer InstituteKaryn J. Brundige - Boston Children's HospitalSuneet Agarwal - Boston Children's HospitalAlison A. Bertuch - Baylor College of MedicineJane E. Churpek - University of Wisconsin–MadisonLaneshia K. Tague - Washington University in St. LouisF. Brad Johnson - Hospital of the University of PennsylvaniaTimothy S. Olson - Children's Hospital of PhiladelphiaDaria V. Babushok - Hospital of the University of Pennsylvania
- Publication Details
- The Journal of clinical investigation, v 135(8), pp 1-22
- Publisher
- American Society for Clinical Investigation
- Grant note
- AI 055413-19 / ; 5R01HL131744 / ; N/A / Team Telomere and the Penn Orphan Disease Center N/A / ; N/A / Farmor Foundation N/A / Uplifting Athletes and Team Telomere K01HL155231 / ; 2T32HG009495-06 / ; 5R01HL148821 / ;
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Medicine
- Web of Science ID
- WOS:001517378500001
- Scopus ID
- 2-s2.0-105003230432
- Other Identifier
- 991022197337104721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Medicine, Research & Experimental