Dietary intervention targets hierarchical metabolic dependencies in human acute myeloid leukemia

Acute myeloid leukemia (AML) is sustained by metabolic plasticity, enabling leukemic cells to adapt across cellular states and withstand therapeutic stress. Whether systemic manipulation of nutrient availability can expose metabolic dependencies in human leukemia remains unknown. We conducted a randomized metabolic intervention in patients with newly diagnosed AML undergoing induction chemotherapy to determine whether short-term carbohydrate restriction could reprogram leukemic metabolism in vivo . Patients received an 8–12-day ketogenic diet (< 10% carbohydrate) during hospitalization. The study was underpowered for its primary clinical endpoint (infection rates) because of recruitment limitations; analyses therefore focused on pre-specified secondary and mechanistic outcomes. Integrating longitudinal plasma metabolomics, proteomics (5,751 proteins), and single-cell transcriptomics (5,101 genes) across more than two million primary cells from over 100 patient samples, we mapped the systemic and cell-state-specific consequences of dietary intervention in AML. Ketogenic diet reduced glucose and insulin exposure while increasing circulating ketones, suppressing ribosome biogenesis, nucleotide synthesis, and anabolic metabolism in proliferative leukemic blasts. These changes were accompanied by adaptive engagement of fatty-acid-supported mitochondrial metabolism. In contrast, stem- and progenitor-like populations implicated in relapse failed to mount comparable adaptive responses, instead exhibiting broad metabolic and transcriptional repression while preserving stemness programs. Together, these findings identify hierarchical metabolic dependencies in human AML and demonstrate that dietary intervention can functionally remodel leukemic cell states in patients. Our study establishes organism-level metabolism as a therapeutic framework for targeting therapy-persistent leukemia populations.