Genetic and epigenetic inactivation of SESTRIN1 controls mTORC1 and response to EZH2 inhibition in follicular lymphoma.
Genetic and epigenetic inactivation of SESTRIN1 controls mTORC1 and response to EZH2 inhibition in follicular lymphoma.
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DOI：
10.1126/scitranslmed.aak9969
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发表时间：
2017-06-28
影响因子：
17.1
通讯作者：
Wendel HG
中科院分区：
文献类型：
--
作者：
Oricchio E;Katanayeva N;Donaldson MC;Sungalee S;Pasion JP;Béguelin W;Battistello E;Sanghvi VR;Jiang M;Jiang Y;Teater M;Parmigiani A;Budanov AV;Chan FC;Shah SP;Kridel R;Melnick AM;Ciriello G;Wendel HG
滤泡性淋巴瘤（FL）是一种无法治愈的B细胞淋巴瘤。基因组学研究已经将FL中常见的遗传病变编目，例如易位t（;），染色体6 q的频繁丢失以及表观遗传调节因子（如EZH 2）的突变。使用集中的遗传筛选，我们确定了SESTRIN 1作为6 q缺失的相关靶点，并证明了SESTRIN 1在体内的肿瘤抑制。此外，SESTRIN 1是淋巴瘤特异性EZH 2功能获得性突变（EZH 2 Y 641 X）的直接靶标。SESTRIN 1失活破坏了p53介导的哺乳动物雷帕霉素复合物靶蛋白1（mTORC 1）的控制，并使基因毒性应激下的mRNA翻译成为可能。SESTRIN 1缺失代表了RRAGC突变的替代，其在营养饥饿下维持mTORC 1活性。药理学EZH 2抑制的抗肿瘤功效取决于SESTRIN 1，表明mTORC 1控制是EZH 2在淋巴瘤中的关键功能。相反，EZH 2 Y 641 X突变淋巴瘤对RapaLink-1（一种双功能mTOR抑制剂）的敏感性增加。因此，SESTRIN 1有助于淋巴瘤中mTORC 1的遗传和表观遗传控制，并影响对靶向治疗的反应。
Follicular lymphoma (FL) is an incurable form of B cell lymphoma. Genomic studies have cataloged common genetic lesions in FL such as translocation t(;), frequent losses of chromosome 6q, and mutations in epigenetic regulators such as EZH2. Using a focused genetic screen, we identified SESTRIN1 as a relevant target of the 6q deletion and demonstrate tumor suppression by SESTRIN1 in vivo. Moreover, SESTRIN1 is a direct target of the lymphoma-specific EZH2 gain-of-function mutation (EZH2Y641X). SESTRIN1 inactivation disrupts p53-mediated control of mammalian target of rapamycin complex 1 (mTORC1) and enables mRNA translation under genotoxic stress. SESTRIN1 loss represents an alternative to RRAGC mutations that maintain mTORC1 activity under nutrient starvation. The antitumor efficacy of pharmacological EZH2 inhibition depends on SESTRIN1, indicating that mTORC1 control is a critical function of EZH2 in lymphoma. Conversely, EZH2Y641X mutant lymphomas show increased sensitivity to RapaLink-1, a bifunctional mTOR inhibitor. Hence, SESTRIN1 contributes to the genetic and epigenetic control of mTORC1 in lymphoma and influences responses to targeted therapies.
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影响因子：
30.8
作者：
Okosun, Jessica;Boedoer, Csaba;Wang, Jun;Araf, Shamzah;Yang, Cheng-Yuan;Pan, Chenyi;Boller, Soeren;Cittaro, Davide;Bozek, Monika;Iqbal, Sameena;Matthews, Janet;Wrench, David;Marzec, Jacek;Tawana, Kiran;Popov, Nikolay;O'Riain, Ciaran;O'Shea, Derville;Carlotti, Emanuela;Davies, Andrew;Lawrie, Charles H.;Matolcsy, Andras;Calaminici, Maria;Norton, Andrew;Byers, Richard J.;Mein, Charles;Stupka, Elia;Lister, T. Andrew;Lenz, Georg;Montoto, Silvia;Gribben, John G.;Fan, Yuhong;Grosschedl, Rudolf;Chelala, Claude;Fitzgibbon, Jude
通讯作者：
Fitzgibbon, Jude
影响因子：
8.8
作者：
Chantranupong L;Wolfson RL;Orozco JM;Saxton RA;Scaria SM;Bar-Peled L;Spooner E;Isasa M;Gygi SP;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
30.8
作者：
Okosun J;Wolfson RL;Wang J;Araf S;Wilkins L;Castellano BM;Escudero-Ibarz L;Al Seraihi AF;Richter J;Bernhart SH;Efeyan A;Iqbal S;Matthews J;Clear A;Guerra-Assunção JA;Bödör C;Quentmeier H;Mansbridge C;Johnson P;Davies A;Strefford JC;Packham G;Barrans S;Jack A;Du MQ;Calaminici M;Lister TA;Auer R;Montoto S;Gribben JG;Siebert R;Chelala C;Zoncu R;Sabatini DM;Fitzgibbon J
通讯作者：
Fitzgibbon J
淋巴瘤中HVEM肿瘤抑制剂的丧失和修饰的CAR-T细胞恢复。
影响因子：
64.5
作者：
Boice M;Salloum D;Mourcin F;Sanghvi V;Amin R;Oricchio E;Jiang M;Mottok A;Denis-Lagache N;Ciriello G;Tam W;Teruya-Feldstein J;de Stanchina E;Chan WC;Malek SN;Ennishi D;Brentjens RJ;Gascoyne RD;Cogné M;Tarte K;Wendel HG
通讯作者：
Wendel HG