Redox metabolism maintains the leukemogenic capacity and drug resistance of AML cells

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.

Automated summary

The rewiring of redox metabolism has a significant impact on tumor development, but the influence of cellular heterogeneity of redox balance on leukemogenesis remains unclear. This study developed a genetically encoded biosensor called HyPerion to track the redox state of leukemic cells in vivo. The findings revealed that a subset of acute myeloid leukemia (AML) cells with low levels of H2O2 (HyPerion-low) was enriched with leukemia-initiating cells, which exhibited high colony-forming ability, potent drug resistance, endosteal localization, and short survival. The high expression of malic enzymes, including ME1/3, accounted for NADPH production and the low abundance of H2O2. Deletion of malic enzymes reduced the population size of leukemia-initiating cells, impairing their leukemogenic capacity and drug resistance.