Abstract
Mutations in the human telomerase reverse transcriptase (TERT) promoter are the most frequent non-coding mutations in cancer, but their molecular mechanism in tumorigenesis has not been established. We used genome editing of human pluripotent stem cells with physiological telomerase expression to elucidate the mechanism by which these mutations contribute to human disease. Surprisingly, telomerase-expressing embryonic stem cells engineered to carry any of the three most frequent TERT promoter mutations showed only a modest increase in TERT transcription with no impact on telomerase activity. However, upon differentiation into somatic cells, which normally silence telomerase, cells with TERT promoter mutations failed to silence TERT expression, resulting in increased telomerase activity and aberrantly long telomeres. Thus, TERT promoter mutations are sufficient to overcome the proliferative barrier imposed by telomere shortening without additional tumor-selected mutations. These data establish that TERT promoter mutations can promote immortalization and tumorigenesis of incipient cancer cells.
Highlights
Activation of telomerase is the critical step for the immortalization of more than 90% of all human tumors (Greider and Blackburn, 1985; Counter, 1992; Kim et al, 1994)
Using genome editing of the endogenous telomerase reverse transcriptase (TERT) locus we generated a panel of three human embryonic stem cells (hESCs) lines that differed exclusively at a single position in the TERT promoter associated with cancer
Analyzing the impact of these mutations in hESCs, we showed that the most frequent mutation, −124C/T, increased TERT mRNA levels in hESCs by about 2–3 fold
Summary
Activation of telomerase is the critical step for the immortalization of more than 90% of all human tumors (Greider and Blackburn, 1985; Counter, 1992; Kim et al, 1994). The physiological events that select for these specific mutations are still unclear, as they have been mostly investigated for their impact in tumor cell lines that are already immortal, maintain telomere length, and have aberrant karyotypes. These tumor cell lines have sufficient telomerase activity to maintain an immortal phenotype, but so do tumor cells without these TERT promoter mutations. Changes in telomerase levels and telomere length provide incomplete information regarding the functional differences between cells that do or do not carry TERT promoter mutations
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