NADPH Metabolism Determines the Leukemogenic Capacity and Drug Resistance of AML Cells

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.