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

Andrew Mancini, Ana Xavier-Magalhães, 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

Research output: Contribution to journalArticle

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. TERT promoter mutations generate a binding site for GABP and reactivate TERT expression. Mancini et al. show that GABPβ1L, among GABP subunits, is specifically required for the function of TERT promoter mutants, and disrupting GABPβ1L causes telomere loss and cell death exclusively in TERT promoter mutant cells.

Original languageEnglish (US)
Pages (from-to)513-528.e8
JournalCancer Cell
Volume34
Issue number3
DOIs
StatePublished - Sep 10 2018

Keywords

  • GABP
  • TERT promoter mutation
  • cancer immortality
  • glioblastoma
  • telomerase
  • telomeres

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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  • Cite this

    Mancini, A., Xavier-Magalhães, A., Woods, W. S., Nguyen, K. T., Amen, A. M., Hayes, J. L., Fellmann, C., Gapinske, M., McKinney, A. M., Hong, C., Jones, L. E., Walsh, K. M., Bell, R. J. A., Doudna, J. A., Costa, B. M., Song, J. S., Perez-Pinera, P., & Costello, J. F. (2018). Disruption of the β1L Isoform of GABP Reverses Glioblastoma Replicative Immortality in a TERT Promoter Mutation-Dependent Manner. Cancer Cell, 34(3), 513-528.e8. https://doi.org/10.1016/j.ccell.2018.08.003