ATM-dependent DNA damage response constrains cell growth and drives clonal hematopoiesis in telomere biology disorders
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.
Authors
- Michael Peterson (ORCID: https://orcid.org/0009-0002-9739-1038)
- D. Mitchell (ORCID: https://orcid.org/0000-0001-9137-1218)
- Daria V. Babushok (ORCID: https://orcid.org/0000-0002-1745-0353)
- Justin P. Rosenheck (ORCID: https://orcid.org/0000-0002-1685-5447)
- Deanne Taylor (ORCID: https://orcid.org/0000-0002-3302-4610)
- Timothy S. Olson (ORCID: https://orcid.org/0000-0003-1288-1960)
- Michael Bowman (ORCID: https://orcid.org/0000-0001-6092-4668)
- Jane E. Churpek (ORCID: https://orcid.org/0000-0001-7998-5479)
- Ping Lin
- Bolormaa Munkhbileg
- Lauren Gabriele Banaszak (ORCID: https://orcid.org/0000-0002-7682-0350)
- Amanda J. Walne (ORCID: https://orcid.org/0000-0001-7184-8808)
- Jennifer J.D. Morrissette (ORCID: https://orcid.org/0000-0001-9460-7177)
- Shannon Zheng
- Ajibike Lapite
- Saar I. Gill (ORCID: https://orcid.org/0000-0001-7946-7778)
- Robert L. Bowman (ORCID: https://orcid.org/0000-0002-8294-8748)
- Daniel C. Link (ORCID: https://orcid.org/0000-0002-3170-7581)
- Sushant Kumar (ORCID: https://orcid.org/0000-0002-7983-6761)
- Christopher M. Sande (ORCID: https://orcid.org/0000-0001-5868-1986)
- Olga Shestova
- Christopher R. Reilly (ORCID: https://orcid.org/0000-0002-9551-7533)
- Suneet Agarwal (ORCID: https://orcid.org/0000-0003-4910-3118)
- Jiayin Zheng (ORCID: https://orcid.org/0000-0002-8960-2790)
- Alison A. Bertuch (ORCID: https://orcid.org/0000-0003-1864-8502)
- Ryan Hausler
- Laneshia K Tague
- Karolyn A. Oetjen (ORCID: https://orcid.org/0000-0002-2846-8831)
- Kelcy Smith‐Simmer (ORCID: https://orcid.org/0000-0001-8611-3265)
- Ritika Dutta
- Stone Chen
- Erica Reinig
- Robert Coleman Lindsley (ORCID: https://orcid.org/0000-0001-9822-806X)
- Inderjeet Dokal (ORCID: https://orcid.org/0000-0003-4462-4782)
- Karyn Brundige
- Natasha Stanley
- Andrew E. Gelman (ORCID: https://orcid.org/0000-0002-0711-6343)
- Diana M. Abraham (ORCID: https://orcid.org/0000-0003-4110-4554)
- Guang Yang (ORCID: https://orcid.org/0000-0002-8430-6917)
- James Corines
- Rujul Jagdish Deolikar
- Mary Zhou
- Jin Cheng (ORCID: https://orcid.org/0000-0002-9095-9869)
- Qijun Chen
- F Brad Johnson
- Kathy Guo
- David Lieberman
- Kyle Shoger
- Peter Nicholas
- Colby Freeman
- Talia Gebhard
Institutions
- Boston Children's Hospital (US)
- Seattle Children's Hospital (US)
- Children's Hospital of Philadelphia (US)
- University of Wisconsin–Madison (US)
- Queen Mary University of London (GB)
- Baylor College of Medicine (US)
- University of Washington (US)
- Washington University in St. Louis (US)
- Hospital of the University of Pennsylvania (US)
- Seattle Children's Hospital (US)
- Dana-Farber Cancer Institute (US)
- Stem Cell Institute (PA)
- Children's Cancer Center (US)
- European Association for Palliative Care (BE)
- The Ohio State University (US)
- Drexel University (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-04-03
- DOI
- https://doi.org/10.1172/jci181659
- Citations
- 7
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 8.15
Funders
- American Society of Hematology
- Leukemia and Lymphoma Society
- Edward P. Evans Foundation
- National Heart, Lung, and Blood Institute
- National Human Genome Research Institute
- National Institute of Allergy and Infectious Diseases