Simple SummaryAcute myeloid leukemia (AML) is a type of cancer that affects blood cells and is the most common type of acute leukemia in adults. Despite advances in treatment, many patients with AML still face poor outcomes, including a high risk of relapse. Therefore, new ways to treat AML are needed. In this study, we have discovered a group of genes called olfactory receptors (ORs) that are highly expressed in AML cells. ORs are normally found in the nose and are responsible for detecting smells, and are not commonly found in other tissues or parts of the body. Here, we show that 19 ORs were predominantly found in AML cells and that the expression of these ORs could predict the prognosis of AML patients. In summary, we believe that these ORs could be further investigated to be used for diagnosis and as targets for new drugs to treat AML.AbstractAcute myeloid leukemia (AML) is the most common form of acute leukemia in adults, with a 5-year overall survival rate of approximately 30%. Despite recent advances in therapeutic options, relapse remains the leading cause of death and poor survival outcomes. New drugs benefit specific small subgroups of patients with actionable therapeutic targets. Thus, finding new targets with greater applicability should be pursued. Olfactory receptors (ORs) are seven transmembrane G-protein coupled receptors preferentially expressed in sensory neurons with a critical role in recognizing odorant molecules. Recent studies have revealed ectopic expression and putative function of ORs in nonolfactory tissues and pathologies, including AML. Here, we investigated OR expression in 151 AML samples, 6400 samples of 15 other cancer types, and 11,200 samples of 51 types of healthy tissues. First, we identified 19 ORs with a distinct and major expression pattern in AML, which were experimentally validated by RT-PCR in an independent set of 13 AML samples, 13 healthy donors, and 8 leukemia cell lines. We also identified an OR signature with prognostic potential for AML patients. Finally, we found cancer-related genes coexpressed with the ORs in the AML samples. In summary, we conducted an extensive study to identify ORs that can be used as novel biomarkers for the diagnosis of AML and as potential drug targets.