文献类型：期刊文献

英文题名：Targeting Bcl-xL is a potential therapeutic strategy for extranodal NK/T cell lymphoma

作者：Liu, Chuanxu[1,3];Ding, Xinyu[2];Li, Gaoyang[2];Zhang, Youping[3];Shao, Yubao[2];Liu, Linyi[2];Zhang, Wenhao[1,3];Ma, Yujie[3];Guan, Wenbin[4];Wang, Lifeng[4];Xu, Zhongli[2];Chang, YungTing[5];Zhang, Yongqiang[6];Jiang, Biao[2,7];Yin, Qianqian[2];Tao, Rong[1,3]

机构：[1]Fudan Univ, Dept Lymphoma, Shanghai Canc Ctr, Shanghai 200032, Peoples R China;[2]ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Sch Life Sci & Technol, Shanghai 201210, Peoples R China;[3]Shanghai Jiao Tong Univ, Xinhua Hosp, Dept Hematol, Sch Med, Shanghai 200092, Peoples R China;[4]Shanghai Jiao Tong Univ, Dept Pathol, Xinhua Hosp, Sch Med, Shanghai 200092, Peoples R China;[5]Shanghai Jiao Tong Univ, Renji Hosp, Dept Pharm, Sch Med, Shanghai 200127, Peoples R China;[6]East China Univ Sci & Technol, Sch Pharm, State Key Lab Bioengn Reactor, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[7]Chinese Acad Sci, Shanghai Inst Organ Chem, CAS Key Lab Synthet Chem Nat Subst, Shanghai 200032, Peoples R China

年份：2023

卷号：26

期号：8

外文期刊名：ISCIENCE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001050126800001)】；

基金：We sincerely appreciate prof. Norio Shimizu at Tokyo Medical and Dental University for providing us with SNK-1, SNK-6, and SNT-8 cells. We are also grateful to the Discovery Technology Platform and Analytical platform of Shanghai Institute for Advanced Immunochemical Studies of ShanghaiTech University for technical assistance with compound screening and flow cytometry experiments; the Molecular Imaging Core Facility platform for the School of Life Science and Technology of ShanghaiTech University for technical assistance with imaging experiment; and the staff members of the National Facility for Protein Science in Shanghai (NFPS) of Zhangjiang Lab for providing technical support and assistance in animal handling, data collection, and analysis. This research was also supported by Shanghai Frontiers Science Center for Biomacromolecules and Precision Medicine at ShanghaiTech University. This work was partially supported by grants from the National Natural Science Foundation of China (82270196 to R.T.; 81873436 to C.-X.L.; 81702600 to Q.-Q.Y.) , the Outstanding Young Medical Talents Program of Shanghai Municipal Health Commission (2017YQ061 to C.-X.L.) , Shanghai Sailing Program (17YF1412200 to Q.-Q.Y.) , the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (20152219 to R.T.) , the Shanghai Science and Technology Commission Grant (18411968300 to R.T.; 23141902900 to C.-X.L.) , and the Shanghai Hospital Development Center Grant (SHDC2019X02 to R.T.) .

语种：英文

摘要：Extranodal natural killer/T cell lymphoma, nasal type (ENKTL) is an aggressive lymphoid malignancy with a poor prognosis and lacks standard treatment. Targeted therapies are urgently needed. Here we systematically investigated the druggable mechanisms through chemogenomic screening and identified that Bcl-xL-specific BH3 mimetics effectively induced ENKTL cell apoptosis. Notably, the specific accumulation of Bcl-xL, but not other Bcl-2 family members, was verified in ENKTL cell lines and patient tissues. Furthermore, Bcl-xL high expression was shown to be closely associated with worse patient survival. The critical role of Bcl-xL in ENKTL cell survival was demonstrated utilizing selective inhibitors, genetic silencing, and a specific degrader. Additionally, the IL2-JAK1/3-STAT5 signaling was implicated in Bcl-xL dysregulation. In vivo, Bcl-xL inhibition reduced tumor burden, increased apoptosis, and prolonged survival in ENKTL cell line xenograft and patient-derived xenograft models. Our study indicates Bcl-xL as a promising therapeutic target for ENKTL, warranting monitoring in ongoing clinical trials by targeting Bcl-xL.