Risk and outcome of Acute Promyelocytic Leukemia (APL) are particularly worsened in obese-overweight individuals, but the underlying molecular mechanism is unknown. In established mouse APL models (Ctsg-PML::RARA), we confirmed that obesity induced by High-Fat Diet (HFD) enhances leukemogenesis by increasing penetrance and shortening latency, providing an ideal model to investigate obesity-induced molecular events in the preleukemic phase. Surprisingly, despite increasing DNA damage in hematopoietic stem cells (HSCs), HFD only minimally increased mutational load, with no relevant impact on known cancer-driving genes . HFD expanded and enhanced self-renewal of hematopoietic progenitor cells (HPC), with concomitant reduction in long-term HSCs. Importantly, Linoleic Acid, abundant in HFD, fully recapitulates the effect of HFD on the self-renewal of PML::RARA HPCs through activation of peroxisome proliferator-activated receptor delta (PPARδ), a central regulator of fatty acid metabolism. Our findings inform dietary/pharmacological interventions to counteract obesity-associated cancers and suggest that nongenetic factors play a key role.