Pooled genetic screens to identify vulnerabilities in TERT-promoter-mutant glioblastoma

Oncogene. 2023 Oct;42(44):3274-3286. doi: 10.1038/s41388-023-02845-w. Epub 2023 Sep 23.


Pooled genetic screens represent a powerful approach to identify vulnerabilities in cancer. Here we used pooled CRISPR/Cas9-based approaches to identify vulnerabilities associated with telomerase reverse transcriptase (TERT) promoter mutations (TPMs) found in >80% of glioblastomas. We first developed a platform to detect perturbations that cause long-term growth defects in a TPM-mutated glioblastoma cell line. However, we could not detect dependencies on either TERT itself or on an E-twenty six transcription (ETS) factor known to activate TPMs. To explore this finding, we cataloged TPM status for 441 cell lines and correlated this with genome-wide screening data. We found that TPM status was not associated with differential dependency on TERT, but that E-twenty six (ETS) transcription factors represent key dependencies in both TPM+ and TPM- lines. Further, we found that TPMs are associated with expression of gene programs regulated by a wide array of ETS-factors in both cell lines and primary glioblastoma tissues. This work contributes a unique TPM cell line reagent, establishes TPM status for many deeply-profiled cell lines, and catalogs TPM-associated vulnerabilities. The results highlight challenges in executing genetic screens to detect TPM-specific vulnerabilities, and suggest redundancy in the genetic network that regulates TPM function with therapeutic implications.

MeSH terms

  • Cell Line, Tumor
  • Gene Regulatory Networks
  • Glioblastoma* / genetics
  • Humans
  • Mutation
  • Promoter Regions, Genetic / genetics
  • Telomerase* / genetics
  • Transcription Factors / genetics


  • Transcription Factors
  • Telomerase
  • TERT protein, human