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Inactivation of the ATMIN/ATM pathway protects against glioblastoma formation.

TitleInactivation of the ATMIN/ATM pathway protects against glioblastoma formation.
Publication TypeJournal Article
Year of Publication2016
AuthorsBlake SM, Stricker SH, Halavach H, Poetsch AR, Cresswell G, Kelly G, Kanu N, Marino S, Luscombe NM, Pollard SM, Behrens A
Date Published2016 Mar 17
KeywordsAnimals, Ataxia Telangiectasia Mutated Proteins, Disease Models, Animal, Gene Knockout Techniques, Glioblastoma, Humans, Mice, Signal Transduction, Transcription Factors, Tumor Suppressor Protein p53

Glioblastoma multiforme (GBM) is the most aggressive human primary brain cancer. Using a Trp53-deficient mouse model of GBM, we show that genetic inactivation of the Atm cofactor Atmin, which is dispensable for embryonic and adult neural development, strongly suppresses GBM formation. Mechanistically, expression of several GBM-associated genes, including Pdgfra, was normalized by Atmin deletion in the Trp53-null background. Pharmacological ATM inhibition also reduced Pdgfra expression, and reduced the proliferation of Trp53-deficient primary glioma cells from murine and human tumors, while normal neural stem cells were unaffected. Analysis of GBM datasets showed that PDGFRA expression is also significantly increased in human TP53-mutant compared with TP53-wild-type tumors. Moreover, combined treatment with ATM and PDGFRA inhibitors efficiently killed TP53-mutant primary human GBM cells, but not untransformed neural stem cells. These results reveal a new requirement for ATMIN-dependent ATM signaling in TP53-deficient GBM, indicating a pro-tumorigenic role for ATM in the context of these tumors.

Alternate JournalElife
PubMed ID26984279
PubMed Central IDPMC4811777
Grant ListG0800020 / / Medical Research Council / United Kingdom
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