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Updated: May 24, 2026
Utilizing Murine Inducible Telomerase Alleles in the Studies of Tissue Degeneration/Regeneration and Cancer
Published on: April 13, 2015
Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer
Jian Hu1, Soyoon Sarah Hwang, Marc Liesa
1Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Abstract:
To assess telomerase as a cancer therapeutic target and determine adaptive mechanisms to telomerase inhibition, we modeled telomerase reactivation and subsequent extinction in T cell lymphomas arising in Atm(-/-) mice engineered with an inducible telomerase reverse transcriptase allele. Telomerase reactivation in the setting of telomere dysfunction enabled full malignant progression with alleviation of telomere dysfunction-induced checkpoints. These cancers possessed copy number alterations targeting key loci in human T cell lymphomagenesis. Upon telomerase extinction, tumor growth eventually slowed with reinstatement of telomere dysfunction-induced checkpoints, yet growth subsequently resumed as tumors acquired alternative lengthening of telomeres (ALT) and aberrant transcriptional networks centering on mitochondrial biology and oxidative defense. ALT+ tumors acquired amplification/overexpression of PGC-1β, a master regulator of mitochondrial biogenesis and function, and they showed marked sensitivity to PGC-1β or SOD2 knockdown. Genetic modeling of telomerase extinction reveals vulnerabilities that motivate coincidental inhibition of mitochondrial maintenance and oxidative defense mechanisms to enhance antitelomerase cancer therapy.
Insights
Inhibiting telomerase in T cell lymphomas can lead to cancer adaptation through alternative lengthening of telomeres (ALT). Targeting ALT pathways, like PGC-1β, alongside telomerase inhibition may improve cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Telomerase is crucial for cancer cell proliferation by maintaining telomere length.
- Understanding adaptive mechanisms to telomerase inhibition is vital for developing effective cancer therapies.
Purpose of the Study:
- To evaluate telomerase as a cancer therapeutic target.
- To investigate adaptive mechanisms, including alternative lengthening of telomeres (ALT), in response to telomerase inhibition.
Main Methods:
- Modeled telomerase reactivation and extinction in engineered Atm(-/-) mice with inducible telomerase reverse transcriptase.
- Analyzed copy number alterations and transcriptional networks in developing T cell lymphomas.
Main Results:
- Telomerase reactivation promoted malignant progression and bypassed checkpoints.
- Telomerase extinction initially slowed tumor growth but was followed by ALT acquisition.
- ALT+ tumors exhibited amplified PGC-1β and sensitivity to PGC-1β/SOD2 knockdown.
Conclusions:
- Telomerase inhibition can drive ALT-mediated cancer adaptation.
- Co-targeting mitochondrial biogenesis (PGC-1β) and oxidative defense (SOD2) with telomerase inhibitors may enhance anti-cancer strategies.
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