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

doi:10.1016/j.isci.2023.107369

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

iScience. 2023 Jul 13;26(8):107369. doi: 10.1016/j.isci.2023.107369. eCollection 2023 Aug 18.

Authors

Chuanxu Liu^{1

2}, Xinyu Ding³, Gaoyang Li³, Youping Zhang², Yubao Shao³, Linyi Liu³, Wenhao Zhang^{1

2}, Yujie Ma², Wenbin Guan⁴, Lifeng Wang⁴, Zhongli Xu³, YungTing Chang⁵, Yongqiang Zhang⁶, Biao Jiang^{3

7}, Qianqian Yin³, Rong Tao^{1

2}

Affiliations

¹ Department of Lymphoma, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
² Department of Hematology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
³ Shanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
⁴ Department of Pathology, Xinhua Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
⁵ Department of Pharmacy, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
⁶ 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.
⁷ CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.

Abstract

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.

Keywords: Biochemistry; Biological sciences; Cancer systems biology; Natural sciences; Systems biology.