Leptin is enriched in bone marrow adipose tissue, but its impact on therapeutic response in acute myeloid leukemia (AML) remains incompletely elucidated. Here, we report that in MLL-AF9 mouse model, exogenous leptin significantly compromised the cytotoxicity of Ara-C, whereas a high-affinity leptin receptor antagonist, Allo-aca, restored chemosensitivity without altering basal leukemia growth, accompanied by marked alterations in mitochondria-associated proteins.