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