TY  - JOUR
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  - Wößmann, 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
TI  - ATM activity in T cells is critical for immune surveillance of lymphoma in vivo.
JO  - Leukemia
VL  - 34
IS  - 3
SN  - 0887-6924
CY  - London
PB  - Springer Nature
M1  - DZNE-2020-00415
SP  - 771-786
PY  - 2020
AB  - 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.
KW  - Alleles
KW  - Animals
KW  - Ataxia Telangiectasia Mutated Proteins: metabolism
KW  - Cell Proliferation
KW  - Etoposide: pharmacology
KW  - Hematopoietic Stem Cell Transplantation
KW  - Lymphoma: immunology
KW  - Lymphoma: metabolism
KW  - Mice
KW  - Mice, Knockout
KW  - T-Lymphocytes: immunology
KW  - T-Lymphocytes: metabolism
KW  - Transplantation, Homologous
KW  - Treatment Outcome
LB  - PUB:(DE-HGF)16
C6  - pmid:31690822
DO  - DOI:10.1038/s41375-019-0618-2
UR  - https://pub.dzne.de/record/145055
ER  -