Redox metabolism maintains the leukemogenic capacity and drug resistance of AML cells
Dan Huang, Changcheng Zhang, Ming Xiao, Li Xie, Weicai Chen, Yu Jiang, Yamin Yuan, Ya‐Ping Zhang, Yejun Zou, Lei Deng, Yang Wang, Yuying Sun, Wenping Dong, Zhuo Zhang, Li Xie, Zhuo Yu, Chiqi Chen, Ligen Liu, Jing Wang, Yi Yang, Jie Yang, Yuzheng Zhao, Junke Zheng
Abstract
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 H 2 O 2 (named HyPerion) and tracked the redox state of leukemic cells in situ in a transgenic sensor mouse. A H 2 O 2 -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 H 2 O 2 . 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.