TSPAN32 suppresses chronic myeloid leukemia pathogenesis and progression by stabilizing PTEN

作     者：Qiang Qiu Yuanyuan Sun Linyu Yang Qingqing Li Yunyu Feng Mengyuan Li Yuexia Yin Li Zheng Ning Li Huandi Qiu Xue Cui Wei He Bochuan Wang Cong Pan Zi Wang Juan Huang Klarke MSample Zhihui Li Yiguo Hu Qiang Qiu;Yuanyuan Sun;Linyu Yang;Qingqing Li;Yunyu Feng;Mengyuan Li;Yuexia Yin;Li Zheng;Ning Li;Huandi Qiu;Xue Cui;Wei He;Bochuan Wang;Cong Pan;Zi Wang;Juan Huang;Klarke M.Sample;Zhihui Li;Yiguo Hu

作者机构：Department of Thyroid SurgeryNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduSichuanChina State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan Universityand Collaborative Innovation Center for BiotherapyChengduSichuanChina Department of OncologyGuizhou Provincial People’s HospitalGuiyangGuizhouChina Sichuan Provincial People’s HospitalChengduSichuanChina Institute of Life ScienceeBond Pharmaceutical Technology Ltd.ChengduChina Laboratory of thyroid and parathyroid diseaseFrontiers Science Center for Disease-related Molecular NetworkWest China HospitalSichuan UniversityChengduSichuanChina Department of Thyroid SurgeryWest China HospitalSichuan UniversityChengduSichuanChina 

出 版 物：《Signal Transduction and Targeted Therapy》 (信号转导与靶向治疗（英文）)

年 卷 期：2023年第8卷第4期

页      面：1814-1827页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：the State Key Laboratory of Biotherapy&Collaborative Innovation Center for Biotherapy for support the staff of the core facility and the animal facility of the State Key Laboratory of Biotherapy and West China Hospital.This work was supported by grants from the National Natural Science Foundation of China(82200152,81770103) National Clinical Research Center for Geriatrics,West China Hospital,Sichuan University(Z20201008) West China Hospital 1.3.5 Project for Disciplines of Excellence(ZYJC18025) Guizhou Provincial Science&Technology Support Program(NO4Y061) The Guizhou Innovation and Entrepreneurship Foundation for High-level Overseas Talent(NO.03) 

主　　题：pathogenesis impaired inhibited 

摘      要：We report herein that TSPAN32 is a key node factor for Philadelphia (Ph+) leukemia pathogenesis. We found that TSPAN32expression was repressed by BCR-ABL and ectopic TSPAN32 expression upon Imatinib treatment inhibited the proliferation of Ph+cell lines. Tspan32 overexpression significantly prevented BCR-ABL induced leukemia progression in a murine model and impairedleukemia stem cell (LSC) proliferation. LSCs represent an obstacle for chronic myeloid leukemia (CML) elimination, which continuallyreplenish leukemia cells and are associated with disease relapse. Therefore, the identification of essential targets that contribute tothe survival and self-renewal of LSCs is important for novel curative CML. Mechanistically, TSPAN32 was shown to interact withPTEN, increased its protein level and caused a reduction in PI3K-AKT signaling activity. We also found that TSPAN32 was repressedby BCR-ABL via the suppression of an important transcription factor, TAL1. Ectopic expression of TAL1 significantly increasedTSPAN32 mRNA and protein level, which indicated that BCR-ABL repressed TSPAN32 transcription by decreasing TAL1 ***, we identified a new signaling axis composed of “BCR-ABL-TAL1-TSPAN32-PTEN-PI3K-AKT. Our findings furthercomplement the known mechanisms underlying the transformation potential of BCR-ABL in CML pathogenesis. This new signalingaxis also provides a potential means to target PI3K-AKT for CML treatment.