Abstract
The mechanism by which redox metabolism regulates the fates of acute myeloid leukemia (AML) cells remains largely unknown. Using a highly sensitive, genetically-encoded fluorescent sensor of nicotinamide adenine dinucleotide phosphate (NADPH), iNap1, we found three heterogeneous subpopulations of AML cells with different NADPH levels in an MLL-AF9-induced murine AML model. The iNap1-high AML cells had enhanced proliferation capacities both in vitro and in vivo and were enriched for more functional leukemia-initiating cells (LICs) than their iNap1-low counterparts. Different NADPH levels in AML cells were also closely associated with their localization in the endosteal niche of bone marrow and chemotherapeutic resistance to methotrexate (MTX). Furthermore, iNap1-high human primary AML cells had enhanced proliferation abilities both in vitro and in vivo. Mechanistically, the MTHFD1-mediated folate cycle regulated NADPH homeostasis to promote leukemogenesis and MTX resistance. These results provide a new perspective for understanding mechanisms by which redox metabolism regulates cancer cell fate and provide a unique metabolic target for potential AML treatments.
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