Acute Myeloid Leukemia Expresses a Specific Group of Olfactory Receptors

Abstract

Acute 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.

Discovery of (−)-epigallocatechin gallate, a novel olfactory receptor 2AT4 agonist that regulates proliferation and apoptosis in leukemia cells

“…ORs in various cancers regulate cancer cell invasiveness, metastasis, and differentiation, and are associated with cellular signaling, proliferation, and apoptosis [ 15 , 48 ]. Among the 19 types of ORs, OR2AE1, OR52B6, and OR2L3 are predominantly expressed in AML samples [ 19 ]. K562 is an immortalized human myeloid leukemia cell line.…”

“…Acute myeloid leukemia (AML) is an aggressive cancer of the hematopoietic progenitor cells that results in uncontrolled clonal proliferation of immature myeloid blast cells [ 18 ]. ORs are highly expressed in AML samples, with 19 ORs co-expressed with cancer marker genes [ 19 ]. In particular, OR2AT4 and OR51B5 were expressed in the K562 cell line and in the white blood cells of patients with AML [ 3 , 20 ].…”

Role of Ectopic Olfactory Receptors in the Regulation of the Cardiovascular–Kidney–Metabolic Axis

“…Therefore, any modulation of inflammatory cell functions through ectopic OR signaling is very likely to affect the cardiovascular-kidney-metabolic axis. While we still know very little about the extent of the repertoire of OR genes that are functionally expressed in leukocytes, it is noteworthy that several ORs were recently found to be highly expressed in acute myeloid leukemia (AML) cells in a pattern that could predict the prognosis of patients [86]. Moreover, activation of the olfactory receptor OR2AT4 (Olfr520) on leukemia cells with the synthetic agonist sandalore has been shown to inhibit cell proliferation and promote apoptosis through Ca 2+dependent activation of Erk1/2 [87].…”