Targeting Bcl-xL is a potential therapeutic strategy for extranodal NK/T cell lymphoma
Chuanxu Liu,
Xinyu Ding,
Gaoyang Li,
Youping Zhang,
Yubao Shao,
Linyi Liu,
Wenhao Zhang,
Yujie Ma,
Wenbin Guan,
Lifeng Wang,
Zhongli Xu,
YungTing Chang,
Yongqiang Zhang,
Biao Jiang,
Qianqian Yin,
Rong Tao
Affiliations
Chuanxu Liu
Department of Lymphoma, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Hematology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Xinyu Ding
Shanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Gaoyang Li
Shanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Youping Zhang
Department of Hematology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Yubao Shao
Shanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Linyi Liu
Shanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Wenhao Zhang
Department of Lymphoma, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Hematology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Yujie Ma
Department of Hematology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Wenbin Guan
Department of Pathology, Xinhua Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Lifeng Wang
Department of Pathology, Xinhua Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Zhongli Xu
Shanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
YungTing Chang
Department of Pharmacy, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
Yongqiang Zhang
State Key Laboratory of Bioengineering Reactor, Shanghai Key Laboratory of New Drug Design and School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
Biao Jiang
Shanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China; Corresponding author
Qianqian Yin
Shanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Corresponding author
Rong Tao
Department of Lymphoma, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Hematology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Corresponding author
Summary: 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.
