| First Author | Hu J | Year | 2012 |
| Journal | Cell | Volume | 148 |
| Issue | 4 | Pages | 651-63 |
| PubMed ID | 22341440 | Mgi Jnum | J:181456 |
| Mgi Id | MGI:5311480 | Doi | 10.1016/j.cell.2011.12.028 |
| Citation | Hu J, et al. (2012) Antitelomerase Therapy Provokes ALT and Mitochondrial Adaptive Mechanisms in Cancer. Cell 148(4):651-63 |
| abstractText | 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-1beta, a master regulator of mitochondrial biogenesis and function, and they showed marked sensitivity to PGC-1beta 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. |
