Riabinska, Arina, Lehrman, Daria, Jachimowicz, Ron Daniel, Knitter, Gero, Fritz, Christian, Schmitt, Anna, Geyer, Aenne, Heneweer, Carola, Wittersheim, Maike, Frenzel, Lukas P., Torgovnick, Alessandro, Wiederstein, Janica Lea, Wunderlich, Claudia Maria, Ortmann, Monika, Paillard, Arlette, Woessmann, Wilhelm, Borkhardt, Arndt, Burdach, Stefan, Hansmann, Martin-Leo, Rosenwald, Andreas, Perner, Sven, Mall, Gita, Klapper, Wolfram, Merseburg, Andrea, Krueger, Marcus, Gruell, Holger, Persigehl, Thorsten, Wunderlich, Frank Thomas, Peifer, Martin, Utermoehlen, Olaf, Buettner, Reinhard, Beleggia, Filippo ORCID: 0000-0003-0234-7094 and Reinhardt, Hans Christian (2020). ATM activity in T cells is critical for immune surveillance of lymphoma in vivo. Leukemia, 34 (3). S. 771 - 787. LONDON: SPRINGERNATURE. ISSN 1476-5551

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Riabinska, ArinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lehrman, DariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jachimowicz, Ron DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knitter, GeroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fritz, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Geyer, AenneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heneweer, CarolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wittersheim, MaikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frenzel, Lukas P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Torgovnick, AlessandroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wiederstein, Janica LeaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wunderlich, Claudia MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ortmann, MonikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Paillard, ArletteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Woessmann, WilhelmUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borkhardt, ArndtUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burdach, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hansmann, Martin-LeoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosenwald, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perner, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mall, GitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klapper, WolframUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merseburg, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gruell, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Persigehl, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wunderlich, Frank ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Utermoehlen, OlafUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beleggia, FilippoUNSPECIFIEDorcid.org/0000-0003-0234-7094UNSPECIFIED
Reinhardt, Hans ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-342915
DOI: 10.1038/s41375-019-0618-2
Journal or Publication Title: Leukemia
Volume: 34
Number: 3
Page Range: S. 771 - 787
Date: 2020
Publisher: SPRINGERNATURE
Place of Publication: LONDON
ISSN: 1476-5551
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DNA-DAMAGE; PURKINJE-CELLS; DEFICIENT MICE; ATAXIA; THERAPY; PROTEIN; GENE; LYMPHOCYTES; LEADS; TRANSPLANTATIONMultiple languages
Oncology; HematologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/34291

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