Abstract
The proximal DNA damage response kinase ATM is frequently inactivated in human malignancies. Germline mutations in the ATM gene cause Ataxia-telangiectasia (A-T), characterized by cerebellar ataxia and cancer predisposition. Whether ATM deficiency impacts on tumor initiation or also on the maintenance of the malignant state is unclear. Here, we show that Atm reactivation in initially Atm-deficient B- and T cell lymphomas induces tumor regression. We further find a reduced T cell abundance in B cell lymphomas from Atm-defective mice and A-T patients. Using T cell-specific Atm-knockout models, as well as allogeneic transplantation experiments, we pinpoint impaired immune surveillance as a contributor to cancer predisposition and development. Moreover, we demonstrate that Atm-deficient T cells display impaired proliferation capacity upon stimulation, due to replication stress. Altogether, our data indicate that T cell-specific restoration of ATM activity or allogeneic hematopoietic stem cell transplantation may prevent lymphomagenesis in A-T patients.
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References
Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461:1071–8.
Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J, et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science. 2007;316:1160–6.
Shiloh Y, Ziv Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol. 2013;14:197–210.
Jachimowicz RD, Beleggia F, Isensee J, Velpula BB, Goergens J, Bustos MA, et al. UBQLN4 represses homologous recombination and is overexpressed in aggressive tumors. Cell. 2019;176:505–19.e22. https://doi.org/10.1016/j.cell.2018.11.024. Epub 3 Jan 2019.
Shiloh Y, Lederman HM. Ataxia-telangiectasia (A-T): an emerging dimension of premature ageing. Ageing Res Rev. 2017;33:76–88. https://doi.org/10.1016/j.arr.2016.05.002. Epub 12 May 2016.
Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science. 1995;268:1749–53.
Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502:333–9.
Zack TI, Schumacher SE, Carter SL, Cherniack AD, Saksena G, Tabak B, et al. Pan-cancer patterns of somatic copy number alteration. Nat Genet. 2013;45:1134–40.
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–21.
Perkhofer L, Schmitt A, Romero Carrasco MC, Ihle M, Hampp S, Ruess DA, et al. ATM deficiency generating genomic instability sensitizes pancreatic ductal adenocarcinoma cells to therapy-induced DNA damage. Cancer Res. 2017;77:5576–90. https://doi.org/10.1158/0008-5472.CAN-17-0634. Epub 8 Aug 2017.
Schmitt A, Knittel G, Welcker D, Yang TP, George J, Nowak M, et al. ATM deficiency is associated with sensitivity to PARP1 and ATR inhibitors in lung adenocarcinoma. Cancer Res. 2017;77:3040–56. https://doi.org/10.1158/0008-5472.CAN-16-3398. Epub 31 Mar 2017.
Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, et al. Restoration of p53 function leads to tumour regression in vivo. Nature. 2007;445:661–5.
Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 2007;445:656–60.
Sakai W, Swisher EM, Karlan BY, Agarwal MK, Higgins J, Friedman C, et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature. 2008;451:1116–20.
Edwards SL, Brough R, Lord CJ, Natrajan R, Vatcheva R, Levine DA, et al. Resistance to therapy caused by intragenic deletion in BRCA2. Nature. 2008;451:1111–5.
Siliciano JD, Canman CE, Taya Y, Sakaguchi K, Appella E, Kastan MB. DNA damage induces phosphorylation of the amino terminus of p53. Genes Dev. 1997;11:3471–81.
Reinhardt HC, Yaffe MB. Phospho-Ser/Thr-binding domains: navigating the cell cycle and DNA damage response. Nat Rev Mol Cell Biol. 2013;14:563–80.
Wang X, Andreassen PR, D’Andrea AD. Functional interaction of monoubiquitinated FANCD2 and BRCA2/FANCD1 in chromatin. Mol Cell Biol. 2004;24:5850–62.
Bahassi EM, Ovesen JL, Riesenberg AL, Bernstein WZ, Hasty PE, Stambrook PJ. The checkpoint kinases Chk1 and Chk2 regulate the functional associations between hBRCA2 and Rad51 in response to DNA damage. Oncogene. 2008;27:3977–85.
Nowak-Wegrzyn A, Crawford TO, Winkelstein JA, Carson KA, Lederman HM. Immunodeficiency and infections in ataxia-telangiectasia. J Pediatr. 2004;144:505–11.
Genik PC, Bielefeldt-Ohmann H, Liu X, Story MD, Ding L, Bush JM, et al. Strain background determines lymphoma incidence in Atm knockout mice. Neoplasia. 2014;16:129–36.
Barlow C, Hirotsune S, Paylor R, Liyanage M, Eckhaus M, Collins F, et al. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell. 1996;86:159–71.
Xu Y, Ashley T, Brainerd EE, Bronson RT, Meyn MS, Baltimore D. Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev. 1996;10:2411–22.
Gage BM, Alroy D, Shin CY, Ponomareva ON, Dhar S, Sharma GG, et al. Spontaneously immortalized cell lines obtained from adult Atm null mice retain sensitivity to ionizing radiation and exhibit a mutational pattern suggestive of oxidative stress. Oncogene. 2001;20:4291–7.
Shiloh Y, Tabor E, Becker Y. Abnormal response of ataxia-telangiectasia cells to agents that break the deoxyribose moiety of DNA via a targeted free radical mechanism. Carcinogenesis. 1983;4:1317–22.
Borghesani PR, Alt FW, Bottaro A, Davidson L, Aksoy S, Rathbun GA, et al. Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice. Proc Natl Acad Sci USA. 2000;97:3336–41.
Li J, Chen J, Vinters HV, Gatti RA, Herrup K. Stable brain ATM message and residual kinase-active ATM protein in ataxia-telangiectasia. J Neurosci. 2011;313:7568–77.
Crawford TO. Ataxia telangiectasia. Semin Pediatr Neurol. 1998;5:287–94.
Bottini AR, Gatti RA, Wirenfeldt M, Vinters HV. Heterotopic Purkinje cells in ataxia-telangiectasia. Neuropathol: Off J Jpn Soc Neuropathol. 2012;32:23–29.
Elson A, Wang Y, Daugherty CJ, Morton CC, Zhou F, Campos-Torres J, et al. Pleiotropic defects in ataxia-telangiectasia protein-deficient mice. Proc Natl Acad Sci USA. 1996;93:13084–9.
Utermohlen O, Schulze-Garg C, Warnecke G, Gugel R, Lohler J, Deppert W. Simian virus 40 large-T-antigen-specific rejection of mKSA tumor cells in BALB/c mice is critically dependent on both strictly tumor-associated, tumor-specific CD8(+) cytotoxic T lymphocytes and CD4(+) T helper cells. J Virol. 2001;75:10593–602.
Patrussi L, Baldari CT. Intracellular mediators of CXCR4-dependent signaling in T cells. Immunol Lett. 2008;115:75–82.
Asselin-Labat ML, David M, Biola-Vidamment A, Lecoeuche D, Zennaro MC, Bertoglio J, et al. GILZ, a new target for the transcription factor FoxO3, protects T lymphocytes from interleukin-2 withdrawal-induced apoptosis. Blood. 2004;104:215–23.
Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000;25:25–29.
The Gene Ontology C. Expansion of the Gene Ontology knowledgebase and resources. Nucleic Acids Res. 2017;45(D1):D331–D338.
Akbar AN, Henson SM. Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat Rev Immunol. 2011;11:289–95.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.
Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12:492–9.
Fathman CG, Lineberry NB. Molecular mechanisms of CD4+ T-cell anergy. Nat Rev Immunol. 2007;7:599–609.
Her J, Ray C, Altshuler J, Zheng H, Bunting SF 53BP1 mediates ATR-Chk1 signaling and protects replication forks under conditions of replication stress. Mol Cell Biol. 2018;38:e00472–17.
Toledo LI, Altmeyer M, Rask MB, Lukas C, Larsen DH, Povlsen LK, et al. ATR prohibits replication catastrophe by preventing global exhaustion of RPA. Cell. 2013;155:1088–103.
Zou L, Elledge SJ. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science. 2003;300:1542–8.
Kotsantis P, Petermann E, Boulton SJ. Mechanisms of oncogene-induced replication stress: jigsaw falling into place. Cancer Discov. 2018;8:537–55.
Bienemann K, Burkhardt B, Modlich S, Meyer U, Moricke A, Bienemann K, et al. Promising therapy results for lymphoid malignancies in children with chromosomal breakage syndromes (Ataxia teleangiectasia or Nijmegen-breakage syndrome): a retrospective survey. Br J Haematol. 2011;155:468–76.
Pietzner J, Baer PC, Duecker RP, Merscher MB, Satzger-Prodinger C, Bechmann I, et al. Bone marrow transplantation improves the outcome of Atm-deficient mice through the migration of ATM-competent cells. Hum Mol Genet. 2013;22:493–507.
Ussowicz M, Musial J, Duszenko E, Haus O, Kalwak K. Long-term survival after allogeneic-matched sibling PBSC transplantation with conditioning consisting of low-dose busilvex and fludarabine in a 3-year-old boy with ataxia-telangiectasia syndrome and ALL. Bone Marrow Transpl. 2013;48:740–1.
Ribeil JA, Hacein-Bey-Abina S, Payen E, Magnani A, Semeraro M, Magrin E, et al. Gene therapy in a patient with sickle cell disease. N Engl J Med. 2017;376:848–55.
Knittel G, Liedgens P, Korovkina D, Seeger JM, Al-Baldawi Y, Al-Maarri M, et al. B cell-specific conditional expression of Myd88p.L252P leads to the development of diffuse large B cell lymphoma in mice. Blood. 2016;127:2732–41. https://doi.org/10.1182/blood-2015-11-684183. Epub 5 Apr 2016.
Knittel G, Rehkamper T, Korovkina D, Liedgens P, Fritz C, Torgovnick A, et al. Two mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia. Nat Commun. 2017;8:153.
Acknowledgements
This work was supported through the Cologne Center for Genomics of the University of Cologne. We thank Prof. Peter Nürnberg, Dr. Janine Altmüller and Dr. Graziella Bosco (University of Cologne, Germany) for help with RNA- and whole exome sequencing.
Financial support
This work was supported by the Volkswagenstiftung (Lichtenberg Program, HCR), the Deutsche Forschungsgemeinschaft (KFO-286, LPF and HCR, JA 2439/1-1 to RDJ), the Bundesministerium für Bildung und Forschung (SMOOSE, HCR), the German federal state NRW (EFRE initiative, LS-1-1-030a, HCR), the Else Kröner-Fresenius Stiftung (EKFS-2014-A06, HCR, 2016-Kolleg-19 to RDJ), the Deutsche Krebshilfe (111724, HCR) and the Jose Carreras Stiftung (DJCLS-R12/26, LPF and HCR).
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HCR received consulting fees from Abbvie, AstraZeneca, Vertex, and Merck and research funding from Gilead. The remaining authors declare that they have no conflict of interest.
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Riabinska, A., Lehrmann, D., Jachimowicz, R.D. et al. ATM activity in T cells is critical for immune surveillance of lymphoma in vivo. Leukemia 34, 771–786 (2020). https://doi.org/10.1038/s41375-019-0618-2
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DOI: https://doi.org/10.1038/s41375-019-0618-2
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