Tumor genotype dictates radiosensitization after Atm deletion in primary brainstem glioma models
Katherine Deland, … , Oren J. Becher, David G. Kirsch
Katherine Deland, … , Oren J. Becher, David G. Kirsch
Published September 29, 2020
Citation Information: J Clin Invest. 2021;131(1):e142158. https://doi.org/10.1172/JCI142158.
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Research Article Oncology

Tumor genotype dictates radiosensitization after Atm deletion in primary brainstem glioma models

Abstract

Diffuse intrinsic pontine glioma (DIPG) kills more children than any other type of brain tumor. Despite clinical trials testing many chemotherapeutic agents, palliative radiotherapy remains the standard treatment. Here, we utilized Cre/loxP technology to show that deleting Ataxia telangiectasia mutated (Atm) in primary mouse models of DIPG can enhance tumor radiosensitivity. Genetic deletion of Atm improved survival of mice with p53-deficient but not p53 wild-type gliomas after radiotherapy. Similar to patients with DIPG, mice with p53 wild-type tumors had improved survival after radiotherapy independent of Atm deletion. Primary p53 wild-type tumor cell lines induced proapoptotic genes after radiation and repressed the NRF2 target, NAD(P)H quinone dehydrogenase 1 (Nqo1). Tumors lacking p53 and Ink4a/Arf expressed the highest level of Nqo1 and were most resistant to radiation, but deletion of Atm enhanced the radiation response. These results suggest that tumor genotype may determine whether inhibition of ATM during radiotherapy will be an effective clinical approach to treat DIPGs.

Authors

Katherine Deland, Bryce F. Starr, Joshua S. Mercer, Jovita Byemerwa, Donna M. Crabtree, Nerissa T. Williams, Lixia Luo, Yan Ma, Mark Chen, Oren J. Becher, David G. Kirsch

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Figure 1

Genetically engineered mouse model of brainstem glioma.

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Genetically engineered mouse model of brainstem glioma. (A) DF1 chicken ...
(A) DF1 chicken fibroblast cells were transfected with RCAS constructs expressing luciferase, PDGFB, or Cre. The virus-producing DF1 cells were injected into the brainstem of neonatal mice. Mice were subjected to biweekly bioluminescence imaging to confirm the presence of a brainstem glioma. Upon tumor detection, mice were stratified to various treatment cohorts. (B) Schematic showing RCAS-Cre–mediated recombination of floxed alleles of Atm and tumor suppressor genes (TSG) in Nestin-expressing neural progenitor cells that harbor the TVA receptor. Triangles represent loxP sites. (C) Axial and (D) sagittal plane views of the glioma enhanced with gadolinium contrast by MRI. Representative glioma stained with (E) H&E or (F) an antibody recognizing the HA tag on PDGFB. Scale bars: 100 μm.