# Telomere maintenance & replicative immortality

Source: https://onco.cc/pathways/telomere-maintenance/  
OnCo record `telomere-maintenance` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Normal cells can divide only a limited number of times because the protective caps on their chromosomes, telomeres, wear down. About 90% of cancers switch the cap-rebuilding enzyme telomerase back on, often through TERT promoter mutations, and roughly 10% use an alternative lengthening route (ALT), so they divide indefinitely; imetelstat is the first approved telomerase inhibitor.

## Summary

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.

## Fields

- Kind: Pathway
- Last checked: 2026-09-08
- Tags: mechanism
- Analogy: 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.
- Interventions: 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

- 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.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Telomerase
- Shay & Wright, Telomeres and telomerase: three decades of progress (Nature Reviews Genetics 2019): https://doi.org/10.1038/s41576-019-0099-1

## Connected records

- targets: [ATR](https://onco.cc/targets/atr/), [ATRX](https://onco.cc/targets/atrx/), [DAXX](https://onco.cc/targets/daxx/), [TERT](https://onco.cc/targets/tert/)
- institutions: [Dana-Farber Brigham Cancer Center](https://onco.cc/institutions/dana-farber/), [Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center](https://onco.cc/institutions/johns-hopkins/), [UCSF Helen Diller Family Comprehensive Cancer Center](https://onco.cc/institutions/ucsf/)
- pathways: [Cellular senescence](https://onco.cc/pathways/senescence/), [DNA replication stress](https://onco.cc/pathways/replication-stress/)
- terms: [Hallmark: enabling replicative immortality](https://onco.cc/terms/enabling-replicative-immortality/), [Hallmarks of cancer as a synthesis of the theories](https://onco.cc/terms/hallmarks-synthesis/), [TERT promoter mutation](https://onco.cc/terms/tert-promoter/)
- key papers: [Telomeres and telomerase: three decades of progress](https://onco.cc/key-papers/paper-shay-nat-rev-genet/)
- technologies: [Epigenetic age after cancer treatment](https://onco.cc/technologies/rejuv-age-epigenetic-clocks/), [Telomere length after treatment](https://onco.cc/technologies/rejuv-age-telomere-length/)

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