ATM-dependent DNA damage response constrains cell growth and drives clonal hematopoiesis in telomere biology disorders
Christopher M. Sande, … , Timothy S. Olson, Daria V. Babushok
Christopher M. Sande, … , Timothy S. Olson, Daria V. Babushok
Published April 3, 2025
Citation Information: J Clin Invest. 2025;135(8):e181659. https://doi.org/10.1172/JCI181659.
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Research Article Hematology Oncology

ATM-dependent DNA damage response constrains cell growth and drives clonal hematopoiesis in telomere biology disorders

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.

Authors

Christopher M. Sande, Stone Chen, Dana V. Mitchell, Ping Lin, Diana M. Abraham, Jessie Minxuan Cheng, Talia Gebhard, Rujul J. Deolikar, Colby Freeman, Mary Zhou, Sushant Kumar, Michael Bowman, Robert L. Bowman, Shannon Zheng, Bolormaa Munkhbileg, Qijun Chen, Natasha L. Stanley, Kathy Guo, Ajibike Lapite, Ryan Hausler, Deanne M. Taylor, James Corines, Jennifer J.D. Morrissette, David B. Lieberman, Guang Yang, Olga Shestova, Saar Gill, Jiayin Zheng, Kelcy Smith-Simmer, Lauren G. Banaszak, Kyle N. Shoger, Erica F. Reinig, Madilynn Peterson, Peter Nicholas, Amanda J. Walne, Inderjeet Dokal, Justin P. Rosenheck, Karolyn A. Oetjen, Daniel C. Link, Andrew E. Gelman, Christopher R. Reilly, Ritika Dutta, R. Coleman Lindsley, Karyn J. Brundige, Suneet Agarwal, Alison A. Bertuch, Jane E. Churpek, Laneshia K. Tague, F. Brad Johnson, Timothy S. Olson, Daria V. Babushok

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Figure 5

Cooccurrence of genetic and clinical outcomes by genotype.

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Cooccurrence of genetic and clinical outcomes by genotype. A cooccurrenc...
A cooccurrence plot with heat map indicating the percentage of tested patients of each genotype demonstrating the specified somatic abnormality or adverse TBD outcome. Patients with multiple germline variants were included both in the individual gene groups and in the multiple variant group. Entries where fewer than 5 total patients were evaluated have been shaded in light gray. A comparison of patients with and without somatic ATM variants is present in the final 2 columns. Because all patients with somatic ATM variants had CH and DDR variants, these categories are shown in dark blue. The corresponding numbers of patients with indicated findings (the numerator) and total number of patients evaluated per category (the denominator) are provided in Supplemental Figure 3.