Targeting Bcl-xL is a potential therapeutic strategy for extranodal NK/T cell lymphoma
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 iden...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223014463 |
| _version_ | 1827893211554643968 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Chuanxu Liu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T21:50:35Z |
| format | Article |
| id | doaj.art-ccbdfdb490734274a1521bd8d01d1dc2 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-12T21:50:35Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-ccbdfdb490734274a1521bd8d01d1dc22023-07-26T04:09:35ZengElsevieriScience2589-00422023-08-01268107369Targeting Bcl-xL is a potential therapeutic strategy for extranodal NK/T cell lymphomaChuanxu Liu0Xinyu Ding1Gaoyang Li2Youping Zhang3Yubao Shao4Linyi Liu5Wenhao Zhang6Yujie Ma7Wenbin Guan8Lifeng Wang9Zhongli Xu10YungTing Chang11Yongqiang Zhang12Biao Jiang13Qianqian Yin14Rong Tao15Department of Lymphoma, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Hematology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, ChinaShanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, ChinaShanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, ChinaDepartment of Hematology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, ChinaShanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, ChinaShanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, ChinaDepartment of Lymphoma, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Hematology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, ChinaDepartment of Hematology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, ChinaDepartment of Pathology, Xinhua Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai 200092, ChinaDepartment of Pathology, Xinhua Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai 200092, ChinaShanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, ChinaDepartment of Pharmacy, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, ChinaState 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, ChinaShanghai 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 authorShanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Corresponding authorDepartment 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004223014463Natural sciencesBiological sciencesBiochemistrySystems biologyCancer systems biology |
| spellingShingle | 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 Targeting Bcl-xL is a potential therapeutic strategy for extranodal NK/T cell lymphoma iScience Natural sciences Biological sciences Biochemistry Systems biology Cancer systems biology |
| title | Targeting Bcl-xL is a potential therapeutic strategy for extranodal NK/T cell lymphoma |
| title_full | Targeting Bcl-xL is a potential therapeutic strategy for extranodal NK/T cell lymphoma |
| title_fullStr | Targeting Bcl-xL is a potential therapeutic strategy for extranodal NK/T cell lymphoma |
| title_full_unstemmed | Targeting Bcl-xL is a potential therapeutic strategy for extranodal NK/T cell lymphoma |
| title_short | Targeting Bcl-xL is a potential therapeutic strategy for extranodal NK/T cell lymphoma |
| title_sort | targeting bcl xl is a potential therapeutic strategy for extranodal nk t cell lymphoma |
| topic | Natural sciences Biological sciences Biochemistry Systems biology Cancer systems biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223014463 |
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