S1P-S1PR3-RAS promotes the progression of S1PR3(hi) TAL1(+) T-cell acute lymphoblastic leukemia that can be effectively inhibited by an S1PR3 antagonist

作者全名："Zhu, Dan; Jiang, Tingting; Ma, Deyu; Zhang, Hongyang; Zhang, Jia; Lv, Wenqiong; Gong, Maoyuan; Wang, Haobiao; Liu, Ziyang; Su, Hongyu; Zeng, Lamei; Liu, Shan; Tang, Shi; Yang, Bijie; Tshavuka, Filippus I.; Fu, Guo; Liu, Zidai; Peng, Danyi; Liu, Haiyan; Yan, Zijun; Cao, Ziyang; Zhao, Hui; He, Tong-Chuan; Yu, Jie; Shu, Yi; Zou, Lin"

作者地址："[Zhu, Dan; Jiang, Tingting; Ma, Deyu; Zhang, Jia; Lv, Wenqiong; Gong, Maoyuan; Wang, Haobiao; Liu, Ziyang; Su, Hongyu; Zeng, Lamei; Liu, Shan; Tang, Shi; Yang, Bijie; Tshavuka, Filippus I.; Fu, Guo; Liu, Zidai; Peng, Danyi; Liu, Haiyan; Yu, Jie; Shu, Yi; Zou, Lin] Chongqing Med Univ, Childrens Hosp, Chongqing Engn Res Ctr Stem Cell Therapy, Ctr Clin Mol Med,Natl Clin Res Ctr Child Hlth & Di, Chongqing, Peoples R China; [Zhang, Hongyang; Yan, Zijun; Cao, Ziyang; Zou, Lin] Shanghai Jiao Tong Univ, Childrens Hosp, Inst Pediat Infect Immun & Crit Care Med, Sch Med,Clin Res Unit, Shanghai, Peoples R China; [Liu, Haiyan; Yu, Jie] Chongqing Med Univ, Div Hematol, Childrens Hosp, Chongqing, Peoples R China; [Zhao, Hui] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Hong Kong, Peoples R China; [Zhao, Hui] Chinese Acad Sci, Kunming Inst Zool, Chinese Univ Hong Kong Joint Lab Bioresources & Mo, Hong Kong, Peoples R China; [Zhao, Hui] Chinese Univ Hong Kong, CAS Ctr Excellence Anim Evolut & Genet, Hong Kong Branch, Hong Kong, Peoples R China; [He, Tong-Chuan] Univ Chicago, Med Ctr, Dept Orthopaed Surg & Rehabil Med, Mol Oncol Lab, Chicago, IL USA"

通信作者："Yu, J; Shu, Y; Zou, L (通讯作者)，Chongqing Med Univ, Childrens Hosp, Chongqing Engn Res Ctr Stem Cell Therapy, Ctr Clin Mol Med,Natl Clin Res Ctr Child Hlth & Di, Chongqing, Peoples R China.; Zou, L (通讯作者)，Shanghai Jiao Tong Univ, Childrens Hosp, Inst Pediat Infect Immun & Crit Care Med, Sch Med,Clin Res Unit, Shanghai, Peoples R China.; Yu, J (通讯作者)，Chongqing Med Univ, Div Hematol, Childrens Hosp, Chongqing, Peoples R China."

来源：LEUKEMIA

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001050416300002

JCR分区：Q1

影响因子：12.8

年份：2023

卷号：　

期号：　

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结束页：　

文献类型：Article; Early Access

关键词：　

摘要："TAL1(+) T-cell acute lymphoblastic leukemia (T-ALL) is a distinct subtype of leukemia with poor outcomes. Through the cooperation of co-activators, including RUNX1, GATA3, and MYB, the TAL1 oncoprotein extends the immature thymocytes with autonomy and plays an important role in the development of T-ALL. However, this process is not yet well understood. Here, by investigating the transcriptome and prognosis of T-ALL from multiple cohorts, we found that S1PR3 was highly expressed in a subset of TAL1(+) T-ALL (S1PR3(hi) TAL1(+) T-ALL), which showed poor outcomes. Through pharmacological and genetic methods, we identified a specific survival-supporting role of S1P-S1PR3 in TAL1(+) T-ALL cells. In T-ALL cells, TAL1-RUNX1 up-regulated the expression of S1PR3 by binding to the enhancer region of S1PR3 gene. With hyperactivated S1P-S1PR3, T-ALL cells grew rapidly, partly by activating the KRAS signal. Finally, we assessed S1PR3 inhibitor TY-52156 in T-ALL patient-derived xenografts (PDXs) mouse model. We found that TY-52156 attenuated leukemia progression efficiently and extended the lifespan of S1PR3(hi) TAL1(+) T-ALL xenografts. Our findings demonstrate that S1PR3 plays an important oncogenic role in S1PR3(hi) TAL1(+) T-ALL and may serve as a promising therapeutic target."

基金机构："National Clinical Research Center for Child Health and Disorders; National Natural Science Foundation of China [81870126, 82070167, 82270160, 81900190]; Chongqing Science and Technology Bureau Major Project [cstc2020jcyj-msxmX0782]"

基金资助正文："We thank the National Clinical Research Center for Child Health and Disorders for the use of their Shared Services (Flow Cytometry Laboratory, Animal Facility, and Experimental Pathology Laboratory) for completing this research. This study was supported by the National Natural Science Foundation of China (#81870126, #82070167, and #82270160 to LZ; #81900190 to YS) and The Chongqing Science and Technology Bureau Major Project (cstc2020jcyj-msxmX0782 to YS). We are grateful to Professors Bing Liu, Yufeng Shi, and Qing Lu for helping us to revise our paper and Figures. Finally, we are greatly indebted to the T-ALL patients and their families for their support and willingness to participate in the study."