机构：[1]Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China[2]Optogenetics & Synthetic Biology Interdisciplinary Research Center, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China[3]Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China[4]Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China[5]Research Unit of New Techniques for Live-Cell Metabolic Imaging, Chinese Academy of Medical Sciences, Beijing 100730, China[6]Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China[7]Department of Pathophysiology, Research Unit of Stress and Cancer Chinese Academy of Medical Sciences, Shanghai Cancer Institute, Renji hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
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 developed 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 subsequent 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.
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 MedicalSciences, 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.
第一作者机构：[1]Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
共同第一作者：
通讯作者：
通讯机构：[1]Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China[2]Optogenetics & Synthetic Biology Interdisciplinary Research Center, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China[5]Research Unit of New Techniques for Live-Cell Metabolic Imaging, Chinese Academy of Medical Sciences, Beijing 100730, China[6]Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China[7]Department of Pathophysiology, Research Unit of Stress and Cancer Chinese Academy of Medical Sciences, Shanghai Cancer Institute, Renji hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
推荐引用方式(GB/T 7714)：
Huang Dan,Zhang Changcheng,Xiao Ming,et al.Redox metabolism maintains the leukemogenic capacity and drug resistance of AML cells[J].PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA.2023,120(13):doi:10.1073/pnas.2210796120.
APA：
Huang Dan,Zhang Changcheng,Xiao Ming,Li Xie,Chen Weicai...&Zheng Junke.(2023).Redox metabolism maintains the leukemogenic capacity and drug resistance of AML cells.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,120,(13)
MLA：
Huang Dan,et al."Redox metabolism maintains the leukemogenic capacity and drug resistance of AML cells".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 120..13(2023)
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