The immortality mechanism of TERT promoter mutant cancers is self-reinforcing and reversible.

Activating mutations in the telomerase reverse transcriptase (TERT) promoter are prevalent in cancer and enable limitless cell division characteristic of immortal cells. Solving the immortality mechanism represents a major step toward selective reversal in cancer cells. TERT promoter (TERTp) mutations create a de novo E26 transformation-specific (ETS) transcription factor binding motif. Here, we analyzed 53 cell lines representing 16 cancer types and 6 recurrent TERTp mutations and found that the GA-binding protein (GABP) tetramer is responsible for promoter activation in all cases. Surprisingly, TERT expression is maintained after tetramer depletion. Further investigation revealed an underlying network of auto-suppression among the GABP subunits. Release from it drives TERT maintenance via upregulated GABP dimers or a paralogous tetramer. The GABPB1L tetramer is therefore a pan-cancer, pan-mutation activator of the mutant TERT promoter, but it is replaceable. Domains shared by the three GABP complexes, rather than solely the B1L tetramer, are mutation-specific vulnerabilities.