The bitter taste receptors: a new mechanism of communication between leukemic cells and the microenvironment

Acute Myeloid Leukemia (AML) is a clonal disease sprouting from a rare population of leukemic stem cells. Increasing interest is gaining the ability of leukemia cells to detect changes in the microenvironment. Bitter taste receptors (T2Rs) are typical G-protein coupled receptors normally located in the oral cavity. Recent studies showed that T2Rs are widely expressed in various tissues where they are involved in the regulation of physiological processes, thus suggesting a wider function in “sensing microenvironment”. In the present thesis, we investigated the T2R role by analyzing AML cell lines, AML primary cells, and normal hematopoietic stem cells (HSCs). T2R activation on leukemia cells with high doses of agonist (Denatonium Benzoate) induced a reduction of cell viability associated with apoptosis induction, while non-toxic doses reduced cell migration and AML clonogenic capacity. In addition, DEN-treatment altered mitochondrial bioenergetic capacity prompted AML cells to a quiescent phenotype and made them more prone to oxidative and metabolic stress. Moreover, we tested the therapeutical potential of DEN with and without chemotherapic agents. Interestingly, we observed that DEN had a synergistic effect with Cytarabine (Ara-C), reducing leukemia cell viability. The combination allowed to reach high toxicity using lower doses of the chemotherapeutic agent. Furthermore, this result was in line with the down-regulation of Ara-C-related multidrug resistance protein expression. Also, we analyzed T2R expression and function on normal HSCs. HSCs expressed several T2R subtypes, and the T2R activation did not affect their viability and did not induce apoptosis, but was involved in the differentiation of HSCs. Indeed, DEN exposure enhanced the engraftment in transplanted mice. In conclusion, our results indicated that T2R receptors were expressed and functional in both leukemic cells and HSCs. These results needed to be further deepened to highlight the off-target effect of T2R activation, and to develop new classes of therapeutic molecules.