Journal Article

DZNE-2020-00415

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png ATM activity in T cells is critical for immune surveillance of lymphoma in vivo.

Riabinska, A. (Corresponding author) ; Lehrmann, D. ; Jachimowicz, R. D. ; Knittel, G. ; Fritz, C. ; Schmitt, A. ; Geyer, A. ; Heneweer, C. ; Wittersheim, M. ; Frenzel, L. P. ; Torgovnick, A. ; Wiederstein, J. L. ; Wunderlich, C. M. ; Ortmann, M. ; Paillard, A. ; Wößmann, W. ; Borkhardt, A. ; Burdach, S. ; Hansmann, M.-L. ; Rosenwald, A. ; Perner, S. ; Mall, G. ; Klapper, W. ; Merseburg, A.DZNE* ; Krüger, M. ; Grüll, H. ; Persigehl, T. ; Wunderlich, F. T. ; Peifer, M. ; Utermöhlen, O. ; Büttner, R. ; Beleggia, F. ; Reinhardt, H. C.

2020
Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s41375-019-0618-2

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.

Keyword(s): Alleles (MeSH) ; Animals (MeSH) ; Ataxia Telangiectasia Mutated Proteins: metabolism (MeSH) ; Cell Proliferation (MeSH) ; Etoposide: pharmacology (MeSH) ; Hematopoietic Stem Cell Transplantation (MeSH) ; Lymphoma: immunology (MeSH) ; Lymphoma: metabolism (MeSH) ; Mice (MeSH) ; Mice, Knockout (MeSH) ; T-Lymphocytes: immunology (MeSH) ; T-Lymphocytes: metabolism (MeSH) ; Transplantation, Homologous (MeSH) ; Treatment Outcome (MeSH)

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Contributing Institute(s):

1. Experimental Neurophysiology (AG Isbrandt)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2020

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Web of Science Core Collection

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