文献类型：期刊文献

英文题名：Redox metabolism maintains the leukemogenic capacity and drug resistance of AML cells

作者：Huang, Dan[1];Zhang, Changcheng[2];Xiao, Ming[3];Li, Xie[2];Chen, Weicai[2];Jiang, Yu[1];Yuan, Yamin[1];Zhang, Yaping[1];Zou, Yejun[2];Deng, Lei[2];Wang, Yang[4];Sun, Yuying[2];Dong, Wenping[2];Zhang, Zhuo[2];Xie, Li[1];Yu, Zhuo[1];Chen, Chiqi[1];Liu, Ligen[1];Wang, Jing[4];Yang, Yi[2];Yang, Jie[3];Zhao, Yuzheng[2,5];Zheng, Junke[1,6,7,8]

机构：[1]Shanghai Jiao Tong Univ, Shanghai Tongren Hosp, Hongqiao Int Inst Med, Sch Med,Key Lab Cell Differentiat & Apoptosis,Chin, Shanghai 200025, Peoples R China;[2]East China Univ Sci & Technol, Optogenet & Synthet Biol Interdisciplinary Res Ctr, Shanghai Frontiers Sci Ctr Optogenet Tech Cell Met, Sch Pharm,State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[3]Shanghai Jiao Tong Univ, Sch Med, Dept Biochem & Mol Cell Biol, Shanghai Key Lab Tumor Microenvironm & Inflammat, Shanghai 200025, Peoples R China;[4]Shanghai Jiao Tong Univ, Sch Med, Dept Immunol & Microbiol, Shanghai 200025, Peoples R China;[5]Chinese Acad Med Sci, Res Unit New Tech Live Cell Metab Imaging, Beijing 100730, Peoples R China;[6]Shanghai Jiao Tong Univ, Sch Med, Shanghai Key Lab Reprod Med, Shanghai 200025, Peoples R China;[7]Shanghai Jiao Tong Univ, Renji Hosp, Canc Chinese Acad Med Sci, Sch Med,Shanghai Canc Inst, Shanghai 200127, Peoples R China;[8]Shanghai Jiao Tong Univ, Renji Hosp, Shanghai Canc Inst, Sch Med,Dept Pathophysiol,Res Unit Stress, Shanghai 200127, Peoples R China

年份：2023

卷号：120

期号：13

外文期刊名：PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001015459700007)】；

基金：This work was supported by grants from National Basic Research Program of China (2019YFA0801800, 2019YFA0904800, and 2018YFA0107000) , National Natural Science Foundation of China (NSFC) (81825001, 32150030, 32030030, 32030065, 31971052, 81900147, 32121005, 92049304, 82000147, 32100906, 82170175, 82200172, and 31900833) , the innovative group of NSFC (81721004) , Shanghai Science and Technology Commission (19XD1422100, 20ZR1430900, 20JC1410100, 20JC1412000, 20204Y0008, and 17ZR1415500) , Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Research Unit of New Techniques for Live-cell Metabolic Imaging (Chinese Academy of Medical Sciences, 2019RU01, 2019-I2M-5-013) , Major Program of Development Fund for Shanghai Zhangjiang National Innovation Demonstration Zone (Stem Cell Strategic Biobank and Stem Cell Clinical Technology Transformation Platform, ZJ2018-ZD-004) , National Postdoctoral Science Foundation of China (2021T140454) , Innovative research team of high-level local universities in Shanghai, the Fundamental Research Funds for the Central Universities, Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (2019-I2M-5-051) , and Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases.

语种：英文

外文关键词：redox metabolism; AML; leukemia-initiating cells; drug resistance

摘要：Rewiring of redox metabolism has a profound impact on tumor development, but how the cellular heterogeneity of redox balance affects leukemogenesis remains unknown. To precisely characterize the dynamic change in redox metabolism in vivo, we devel-oped a bright genetically encoded biosensor for H2O2 (named HyPerion) and tracked the redox state of leukemic cells in situ in a transgenic sensor mouse. A H2O2-low (HyPerion-low) subset of acute myeloid leukemia (AML) cells was enriched with leukemia-initiating cells, which were endowed with high colony-forming ability, potent drug resistance, endosteal rather than vascular localization, and short survival. Significantly high expression of malic enzymes, including ME1/3, accounted for nicotinamide adenine dinucleotide phosphate (NADPH) production and the subse-quent low abundance of H2O2. Deletion of malic enzymes decreased the population size of leukemia-initiating cells and impaired their leukemogenic capacity and drug resistance. In summary, by establishing an in vivo redox monitoring tool at single-cell resolution, this work reveals a critical role of redox metabolism in leukemogenesis and a potential therapeutic target.