Disruption of the β1L Isoform of GABP Reverses Glioblastoma Replicative Immortality in a TERT Promoter Mutation-Dependent Manner

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2018 Sep 12

PMID 30205050

Citations 76

Authors

Andrew Mancini

Ana Xavier-Magalhaes

Wendy S Woods

Kien-Thiet Nguyen

Alexandra M Amen

Josie L Hayes

Christof Fellmann

Michael Gapinske

Andrew M McKinney

Chibo Hong

Lindsey E Jones

Kyle M Walsh

Robert J A Bell

Jennifer A Doudna

Bruno M Costa

Jun S Song

Pablo Perez-Pinera

Joseph F Costello

Affiliations

Soon will be listed here.

Abstract

TERT promoter mutations reactivate telomerase, allowing for indefinite telomere maintenance and enabling cellular immortalization. These mutations specifically recruit the multimeric ETS factor GABP, which can form two functionally independent transcription factor species: a dimer or a tetramer. We show that genetic disruption of GABPβ1L (β1L), a tetramer-forming isoform of GABP that is dispensable for normal development, results in TERT silencing in a TERT promoter mutation-dependent manner. Reducing TERT expression by disrupting β1L culminates in telomere loss and cell death exclusively in TERT promoter mutant cells. Orthotopic xenografting of β1L-reduced, TERT promoter mutant glioblastoma cells rendered lower tumor burden and longer overall survival in mice. These results highlight the critical role of GABPβ1L in enabling immortality in TERT promoter mutant glioblastoma.

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