title: Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer.
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.
authors.affiliation: Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Hu
authors.forename: Soyoon Sarah
authors.initials: SS
authors.lastname: Hwang
authors.forename: Marc
authors.initials: M
authors.lastname: Liesa
authors.forename: Boyi
authors.initials: B
authors.lastname: Gan
authors.forename: Ergun
authors.initials: E
authors.lastname: Sahin
authors.forename: Mariela
authors.initials: M
authors.lastname: Jaskelioff
authors.forename: Zhihu
authors.initials: Z
authors.lastname: Ding
authors.forename: Haoqiang
authors.initials: H
authors.lastname: Ying
authors.forename: Adam T
authors.initials: AT
authors.lastname: Boutin
authors.forename: Hailei
authors.initials: H
authors.lastname: Zhang
authors.forename: Shawn
authors.initials: S
authors.lastname: Johnson
authors.forename: Elena
authors.initials: E
authors.lastname: Ivanova
authors.forename: Maria
authors.initials: M
authors.lastname: Kost-Alimova
authors.forename: Alexei
authors.initials: A
authors.lastname: Protopopov
authors.forename: Yaoqi Alan
authors.initials: YA
authors.lastname: Wang
authors.forename: Orian S
authors.initials: OS
authors.lastname: Shirihai
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D055785:Gene Knockdown Techniques; D018816:Genes, cdc; D006801:Humans; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D059505:Telomere Homeostasis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics; D000099156:Superoxide Dismutase 2
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D013482:Superoxide Dismutase; D019098:Telomerase; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000099156:Superoxide Dismutase 2; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; C576324:ATM protein, human; C576325:Atm protein, mouse