Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Immune Environment in Glioblastoma (Upcoming)
    • Korsmeyer Award 25th Anniversary Collection (Jan 2023)
    • Aging (Jul 2022)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Research letters
    • Letters to the editor
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Research letters
  • Letters to the editor
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
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.
View: Text | PDF
Research Article Oncology

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

  • Text
  • PDF
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

×

Figure 1

Genetically engineered mouse model of brainstem glioma.

Options: View larger image (or click on image) Download as PowerPoint
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.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts