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      Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer.

      Cell
      Animals, Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins, genetics, DNA-Binding Proteins, Gene Knockdown Techniques, Genes, cdc, Humans, Lymphoma, T-Cell, metabolism, pathology, Mice, Mitochondria, Neoplasm Invasiveness, Neoplasms, Protein-Serine-Threonine Kinases, Reactive Oxygen Species, Receptors, Estrogen, Superoxide Dismutase, Telomerase, antagonists & inhibitors, Telomere Homeostasis, Transcription Factors, Tumor Suppressor Proteins

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          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. Copyright © 2012 Elsevier Inc. All rights reserved.

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