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Open Access 01-12-2019 | Glioma | Research

TERT expression is susceptible to BRAF and ETS-factor inhibition in BRAF^V600E/TERT promoter double-mutated glioma

Authors: Lisa Gabler, Daniela Lötsch, Dominik Kirchhofer, Sushilla van Schoonhoven, Hannah M. Schmidt, Lisa Mayr, Christine Pirker, Katharina Neumayer, Carina Dinhof, Lucia Kastler, Amedeo A. Azizi, Christian Dorfer, Thomas Czech, Christine Haberler, Andreas Peyrl, Rajiv Kumar, Irene Slavc, Sabine Spiegl-Kreinecker, Johannes Gojo, Walter Berger

Published in: Acta Neuropathologica Communications | Issue 1/2019

Abstract

The BRAF gene and the TERT promoter are among the most frequently altered genomic loci in low-grade (LGG) and high-grade-glioma (HGG), respectively. The coexistence of BRAF and TERT promoter aberrations characterizes a subset of aggressive glioma. Therefore, we investigated interactions between those alterations in malignant glioma. We analyzed co-occurrence of BRAF^V600E and TERT promoter mutations in our clinical data (n = 8) in addition to published datasets (n = 103) and established a BRAF^V600E-positive glioma cell panel (n = 9) for in vitro analyses. We investigated altered gene expression, signaling events and TERT promoter activity upon BRAF- and E-twenty-six (ETS)-factor inhibition by qRT-PCR, chromatin immunoprecipitation (ChIP), Western blots and luciferase reporter assays. TERT promoter mutations were significantly enriched in BRAF^V600E-mutated HGG as compared to BRAF^V600E-mutated LGG. In vitro, BRAF^V600E/TERT promoter double-mutant glioma cells showed exceptional sensitivity towards BRAF-targeting agents. Remarkably, BRAF-inhibition attenuated TERT expression and TERT promoter activity exclusively in double-mutant models, while TERT expression was undetectable in BRAF^V600E-only cells. Various ETS-factors were broadly expressed, however, only ETS1 expression and phosphorylation were consistently downregulated following BRAF-inhibition. Knock-down experiments and ChIP corroborated the notion of a functional role for ETS1 and, accordingly, all double-mutant tumor cells were highly sensitive towards the ETS-factor inhibitor YK-4-279. In conclusion, our data suggest that concomitant BRAF^V600E and TERT promoter mutations synergistically support cancer cell proliferation and immortalization. ETS1 links these two driver alterations functionally and may represent a promising therapeutic target in this aggressive glioma subgroup.

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Title: TERT expression is susceptible to BRAF and ETS-factor inhibition in BRAFV600E/TERT promoter double-mutated glioma
Authors: Lisa Gabler
Daniela Lötsch
Dominik Kirchhofer
Sushilla van Schoonhoven
Hannah M. Schmidt
Lisa Mayr
Christine Pirker
Katharina Neumayer
Carina Dinhof
Lucia Kastler
Amedeo A. Azizi
Christian Dorfer
Thomas Czech
Christine Haberler
Andreas Peyrl
Rajiv Kumar
Irene Slavc
Sabine Spiegl-Kreinecker
Johannes Gojo
Walter Berger
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Glioma
Glioma
Glioma
Brain Tumor
Published in: Acta Neuropathologica Communications / Issue 1/2019
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-019-0775-6

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TERT expression is susceptible to BRAF and ETS-factor inhibition in BRAF^V600E/TERT promoter double-mutated glioma

Abstract

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Intraventricular meningiomas frequently harbor NF2 mutations but lack common genetic alterations in TRAF7, AKT1, SMO, KLF4, PIK3CA, and TERT

KCC2 expression levels are reduced in post mortem brain tissue of Rett syndrome patients