ATM activity in T cells is critical for immune surveillance of lymphoma in vivo

Leukemia. 2020 Mar;34(3):771-786. doi: 10.1038/s41375-019-0618-2. Epub 2019 Nov 5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Cell Proliferation
  • Etoposide / pharmacology
  • Hematopoietic Stem Cell Transplantation
  • Lymphoma / immunology*
  • Lymphoma / metabolism
  • Mice
  • Mice, Knockout
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Transplantation, Homologous
  • Treatment Outcome

Substances

  • Etoposide
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse