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 12

Clonal architecture and hematopoietic contributions of cells with and without somatic ATM variants in peripheral blood of a TERC-mutated TBD patient analyzed using single-cell DNA and protein sequencing on the Tapestri platform.

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Clonal architecture and hematopoietic contributions of cells with and wi...
(A) Bar graph showing the numbers of cells with the genotypes indicated on the x axis, and the cell types identified by surface protein staining on the y axis. Both of the somatic ATM variants were identified within the same clone. (B) Shown are the relative hematopoietic cell distributions of WT, ATM-mutant, and PPM1D-mutant clones, showing that ATM-mutant and PPM1D-mutant clones were highly skewed to myeloid cells, as compared with cells without either ATM or PPM1D variants. (C–G) UMAP plots depicting the clone distribution of the WT, ATM-, and PPM1D-mutant cells, overlaid in C and shown separately with color coding indicating the corresponding hematopoietic cell subsets. (E–G) Distribution of CD117 (immature myeloid and mast cell marker c-kit), myeloid cell marker CD11b, and T-lymphocyte cell marker CD3 expression, respectively.