Telomere maintenance & replicative immortality
Normal cells can divide only so many times because the protective caps on their chromosomes, telomeres, wear down. Cancers switch the cap-rebuilding enzyme telomerase back on, or find another way (ALT), so they can divide forever.
About 90% of cancers reactivate telomerase (TERT), often via TERT promoter mutations (glioblastoma, melanoma, bladder, thyroid) or amplification; ~10% use alternative lengthening of telomeres (ALT) through homologous recombination, associated with ATRX/DAXX loss (sarcomas, pancreatic NETs, gliomas). Telomerase inhibition (imetelstat, an oligonucleotide) reached approval in lower-risk MDS (2024) and is in phase 3 in myelofibrosis; ALT cells are sensitive to ATR inhibition. TERT promoter mutation is a diagnostic and prognostic marker and a candidate for ctDNA detection in bladder cancer and glioma.
In one picture
The plastic tips on shoelaces fray a little every time you tie them; when they are gone the lace unravels and the shoe is thrown out. Cancer cells carry a machine that keeps re-tipping the laces.
Diagram
top- Imetelstat (telomerase inhibitor) approved in MDS (2024); solid-tumour use unproven
- ATR inhibitors in ALT-positive tumours
- TERT promoter mutation as a urine/plasma biomarker (bladder, glioma)
Notes
top- Leading programmes: Greider (Johns Hopkins, Nobel 2009); Meyerson (Dana-Farber) on TERT promoter genetics; Costello (UCSF) on TERT in glioma; Reddel (CMRI Sydney) on ALT.
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Shares Cellular senescence, Dana-Farber Brigham Cancer Center and the tag mechanism.