Abstract 4946: Bitter taste receptors system is expressed and functional in both HSCs and leukemic cells

Acute Myeloid Leukemia (AML) is a clonal disease developing from a rare population of leukemic stem cells. Alongside the identification of disease-specific alleles harbored by AML clones, the contribution that cell-extrinsic factors have in AML generation and persistence by influencing AML cell genomic landscape and therapy-resistance is gaining increasing interest. In the cross-talk between AML cells and their microenvironment, several membrane receptors sense the external changes by triggering intracellular signals. Among these, the largest group belongs to the family of G protein-couple receptors (GPCRs). Bitter taste receptors (T2Rs) comprise 25 distinct members of the GPCR family. Initially described in the oral cavity, T2Rs are actually widely expressed in different tissues and in various cancer cell types. In the present work, we showed that AML cells expressed fully functional T2R subtypes. Their activation substantially modified the AML cell transcriptomic profile and deregulated relevant cellular processes, resulting in inhibited clonogenic capacity, proliferation and cell motility and induced apoptosis. In addition, T2R stimulation with agonist altered mitochondrial bioenergetic capacity and made AML cells more prone to oxidative and metabolic stress. Given the effect of T2R activation on crucial AML cell function, we tested the therapeutical potential of targeting T2Rs. Interestingly, we observed that T2R stimulation had a synergistic effect with cytarabine, reducing leukemia cell viability and allowing to reach high toxicity using lower doses of chemotherapic agent. Then we analyzed T2Rs expression and function on normal hematopoietic stem cells (HSCs). HSCs expressed several T2R subtypes with some differences compare to AML cells. T2Rs activation didn't affect HSCs viability and motility, conversely to AML cells, but significantly inhibited clonogenic capacity, by reducing the frequency of precursors. Our data may suggest a role for microenvironment “bitter” molecules in regulating normal and leukemic hematopoiesis. Notably, many common drugs, such as antibiotics, chloroquine, haloperidol, procainamide, are bitter tasting and are thus effective ligands for T2Rs. For this reason, they could exhibit an off-target effect in T2R expressing cells, including leukemic and normal hematopoietic cells. Our results may have implications in understanding the off-target actions of diverse drugs and could reveal potential new therapeutic targets Citation Format: Valentina Salvestrini, Valentina Pensato, Marilena Ciciarello, Giorgia Simonetti, Samantha Bruno, Martina Pazzaglia, Elena De Marchi, Dorian Forte, Stefania Orecchioni, Giovanni Martinelli, Francesco Bertolini, Simon Mendez-Ferrer, Elena Adinolfi, Michele Cavo, Antonio Curti. Bitter taste receptors system is expressed and functional in both HSCs and leukemic cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4946.