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ATM activity in T cells is critical for immune surveillance of lymphoma in vivo.
Leukemia 2019L

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.

Authors+Show Affiliations

Clinic I of Internal Medicine, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, 50937, Germany. arina.riabinska@uk-koeln.de.Clinic I of Internal Medicine, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, 50937, Germany.Clinic I of Internal Medicine, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, 50937, Germany.Clinic I of Internal Medicine, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, 50937, Germany.Clinic I of Internal Medicine, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, 50937, Germany.Clinic I of Internal Medicine, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, 50937, Germany.Clinic I of Internal Medicine, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, 50937, Germany.Department of Radiology, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, 50937, Germany.Institute of Pathology, University Hospital of Cologne, Medical Faculty, University of Cologne, Cologne, 50937, Germany.Clinic I of Internal Medicine, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, 50937, Germany. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, 50937, Germany.Clinic I of Internal Medicine, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, 50937, Germany. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, 50937, Germany.Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, 50937, Germany.Max Planck Institute for Metabolism Research, Cologne, 50937, Germany.Institute of Pathology, University Hospital of Cologne, Medical Faculty, University of Cologne, Cologne, 50937, Germany.Intitute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, 50937, Germany.Department of Pediatric Hematology and Oncology, Justus-Liebig-University, Giessen, 35390, Germany.Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Heinrich Heine University, Medical Faculty, Düsseldorf, 40225, Germany.Children's Cancer Research Center and Department of Pediatrics, Rechts der Isar Hospital, Technical University of Munich and Comprehensive Cancer Center Munich, Munich, 80333, Germany.Institute of Pathology, University of Frankfurt, Medical School, Frankfurt, 60590, Germany.Institute of Pathology, University of Würzburg and Comprehensive Cancer Center Mainfranken, Würzburg, 97080, Germany.Institute of Pathology, University Hospital Schleswig-Holstein, Lübeck, 23538, Germany.Institute of Forensic Medicine, University Hospital Jena, Jena, 07743, Germany.Pathology, Hematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Kiel, 24105, Germany.Experimental Neurophysiology, German Center for Neurodegenerative Diseases, Bonn, 53175, Germany.Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, 50937, Germany.Department of Radiology, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, 50937, Germany.Department of Radiology, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, 50937, Germany.Max Planck Institute for Metabolism Research, Cologne, 50937, Germany.Center for Molecular Medicine Cologne, University of Cologne, Cologne, 50937, Germany. Department of Translational Genomics, Cologne, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, 50937, Germany.Intitute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, 50937, Germany. Center for Molecular Medicine Cologne, University of Cologne, Cologne, 50937, Germany. German Center for Infection Research (DZIF), Bonn-Cologne, Cologne, Germany.Institute of Pathology, University Hospital of Cologne, Medical Faculty, University of Cologne, Cologne, 50937, Germany. Center for Molecular Medicine Cologne, University of Cologne, Cologne, 50937, Germany.Clinic I of Internal Medicine, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, 50937, Germany.Clinic I of Internal Medicine, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, 50937, Germany. christian.reinhardt@uk-koeln.de. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, 50937, Germany. christian.reinhardt@uk-koeln.de. Center for Molecular Medicine Cologne, University of Cologne, Cologne, 50937, Germany. christian.reinhardt@uk-koeln.de.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31690822

Citation

Riabinska, Arina, et al. "ATM Activity in T Cells Is Critical for Immune Surveillance of Lymphoma in Vivo." Leukemia, 2019.
Riabinska A, Lehrmann D, Jachimowicz RD, et al. ATM activity in T cells is critical for immune surveillance of lymphoma in vivo. Leukemia. 2019.
Riabinska, A., Lehrmann, D., Jachimowicz, R. D., Knittel, G., Fritz, C., Schmitt, A., ... Reinhardt, H. C. (2019). ATM activity in T cells is critical for immune surveillance of lymphoma in vivo. Leukemia, doi:10.1038/s41375-019-0618-2.
Riabinska A, et al. ATM Activity in T Cells Is Critical for Immune Surveillance of Lymphoma in Vivo. Leukemia. 2019 Nov 5; PubMed PMID: 31690822.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - ATM activity in T cells is critical for immune surveillance of lymphoma in vivo. AU - Riabinska,Arina, AU - Lehrmann,Daria, AU - Jachimowicz,Ron Daniel, AU - Knittel,Gero, AU - Fritz,Christian, AU - Schmitt,Anna, AU - Geyer,Aenne, AU - Heneweer,Carola, AU - Wittersheim,Maike, AU - Frenzel,Lukas P, AU - Torgovnick,Alessandro, AU - Wiederstein,Janica Lea, AU - Wunderlich,Claudia Maria, AU - Ortmann,Monika, AU - Paillard,Arlette, AU - Wöβmann,Wilhelm, AU - Borkhardt,Arndt, AU - Burdach,Stefan, AU - Hansmann,Martin-Leo, AU - Rosenwald,Andreas, AU - Perner,Sven, AU - Mall,Gita, AU - Klapper,Wolfram, AU - Merseburg,Andrea, AU - Krüger,Marcus, AU - Grüll,Holger, AU - Persigehl,Thorsten, AU - Wunderlich,Frank Thomas, AU - Peifer,Martin, AU - Utermöhlen,Olaf, AU - Büttner,Reinhard, AU - Beleggia,Filippo, AU - Reinhardt,Hans Christian, Y1 - 2019/11/05/ PY - 2019/05/13/received PY - 2019/10/24/accepted PY - 2019/09/25/revised PY - 2019/11/7/pubmed PY - 2019/11/7/medline PY - 2019/11/7/entrez JF - Leukemia JO - Leukemia N2 - 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. SN - 1476-5551 UR - https://www.unboundmedicine.com/medline/citation/31690822/ATM_activity_in_T_cells_is_critical_for_immune_surveillance_of_lymphoma_in_vivo L2 - http://dx.doi.org/10.1038/s41375-019-0618-2 DB - PRIME DP - Unbound Medicine ER -