Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer.
Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer.
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DOI：
10.1016/j.cell.2011.12.028
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发表时间：
2012-02-17
期刊：
影响因子：
64.5
通讯作者：
DePinho RA
中科院分区：
文献类型：
--
作者：
Hu J;Hwang SS;Liesa M;Gan B;Sahin E;Jaskelioff M;Ding Z;Ying H;Boutin AT;Zhang H;Johnson S;Ivanova E;Kost-Alimova M;Protopopov A;Wang YA;Shirihai OS;Chin L;DePinho RA
为了评估端粒酶作为癌症治疗靶点并确定端粒酶抑制的适应性机制，我们模拟了端粒酶在诱导型端粒酶逆转录酶等位基因改造的Atm-/-小鼠中产生的t细胞淋巴瘤的端粒酶再激活和随后的消失。端粒功能障碍情况下的端粒酶再激活使完全恶性进展与端粒功能障碍诱导的检查点减轻。这些癌症具有针对人类t细胞淋巴瘤发生过程中关键位点的拷贝数改变。在端粒酶消失后，肿瘤生长最终会随着端粒功能障碍诱导的检查点的重新恢复而减慢，但随着肿瘤获得端粒选择性延长（ALT）和以线粒体生物学和氧化防御为中心的异常转录网络，肿瘤生长随后会恢复。ALT+肿瘤获得了PGC-1β的扩增/过表达，PGC-1β是线粒体生物发生和功能的主要调节因子，并且它们对PGC-1β或SOD2敲除表现出明显的敏感性。端粒酶灭绝的遗传模型揭示了激发线粒体维持和氧化防御机制的巧合抑制的脆弱性，以增强抗端粒酶癌症治疗。
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 re-instatement 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 knock-down. Genetic modeling of telomerase extinction reveals vulnerabilities that motivate coincidental inhibition of mitochondrial maintenance and oxidative defense mechanisms to enhance anti-telomerase cancer therapy.
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影响因子：
56.9
作者：
FENG, JL;FUNK, WD;VILLEPONTEAU, B
通讯作者：
VILLEPONTEAU, B
影响因子：
64.8
作者：
Hall, DB;Holmlin, RE;Barton, JK
通讯作者：
Barton, JK
ATRX和DAXX突变的肿瘤中端粒改变。
DOI：
10.1126/science.1207313
发表时间：
2011-07-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Heaphy CM;de Wilde RF;Jiao Y;Klein AP;Edil BH;Shi C;Bettegowda C;Rodriguez FJ;Eberhart CG;Hebbar S;Offerhaus GJ;McLendon R;Rasheed BA;He Y;Yan H;Bigner DD;Oba-Shinjo SM;Marie SK;Riggins GJ;Kinzler KW;Vogelstein B;Hruban RH;Maitra A;Papadopoulos N;Meeker AK
通讯作者：
Meeker AK
影响因子：
64.8
作者：
Gao, Ping;Tchernyshyov, Irina;Chang, Tsung-Cheng;Lee, Yun-Sil;Kita, Kayoko;Ochi, Takafumi;Zeller, Karen I.;De Marzo, Angelo M.;Van Eyk, Jennifer E.;Mendell, Joshua T.;Dang, Chi V.
通讯作者：
Dang, Chi V.
影响因子：
56.9
作者：
Karlseder, J;Broccoli, D;de Lange, T
通讯作者：
de Lange, T