Https://doi.org/10.18632/oncotarget.13927 Valentina Salvestrini, Stefania Orecchioni, Giovanna Talarico, Francesca Reggiani, Cristina Mazzetti, Francesco Bertolini, Elisa Orioli, Elena Adinolfi,...

The contribution of cell-extrinsic factors in Acute Myeloid Leukemia (AML) generation and persistence has gained interest. Bitter taste receptors (TAS2Rs) are G protein-coupled receptors known for their primary role as a central warning signal to induce aversion toward noxious or harmful substances. Nevertheless, the increasing amount of evidence about their extra-oral localization has suggested a wider function in sensing microenvironment, also in cancer settings. In this study, we found that AML cells express functional TAS2Rs. We also highlighted a significant association between the modulation of some TAS2Rs and the poor-prognosis AML groups, i.e., TP53- and TET2-mutated, supporting a potential role of TAS2Rs in AML cell biology. Gene expression profile analysis showed that TAS2R activation with the prototypical agonist, denatonium benzoate, significantly modulated a number of genes involved in relevant AML cellular processes. Functional assay substantiated molecular data and indicated that denatonium reduced AML cell proliferation by inducing cell cycle arrest in G0/G1 phase or induced apoptosis via caspase cascade activation. Moreover, denatonium exposure impaired AML cell motility and migratory capacity, and inhibited cellular respiration by decreasing glucose uptake and oxidative phosphorylation. In conclusion, our results in AML cells expand the observation of cancer TAS2R expression to the setting of hematological neoplasms and shed light on a role of TAS2Rs in the extrinsic regulation of leukemia cell functions.

Background: The management of acute myeloid leukemia (AML) is hindered by treatment‐related toxicities and complications, particularly cytopenia, which remains a leading cause of mortality. Given the pivotal role of the gut microbiota (GM) in hemopoiesis and immune regulation, we investigated its impact on hematologic recovery during AML induction therapy.Methods: We profiled the GM of 27 newly diagnosed adult AML patients using 16S rRNA amplicon sequencing and correlated it with key clinical parameters before and after induction therapy.Results: Our investigation revealed intriguing associations between the GM composition and crucial recovery indicators, including platelet, lymphocyte, and neutrophil counts, and identified early GM signatures predictive of improved hematologic recovery. Remarkably, patients demonstrating superior recovery had higher alpha diversity and enrichment in health‐associated taxa belonging to the genera Faecalibacterium, Ruminococcus, Blautia, and Butyricimonas at diagnosis.Conclusions: Despite certain study limitations, our findings suggest that evaluating GM features could serve as a potential marker for hematologic recovery. This preliminary work opens avenues for personalized risk assessment and interventions, possibly involving GM modulation tools, to optimize recovery in AML patients undergoing induction therapy and potentially enhancing overall outcomes in individuals with hematologic diseases.

Bone marrow microenvironmental stimuli profoundly impact hematopoietic stem cell fate and biology. As G protein-coupled receptors, the bitter taste receptors (TAS2Rs) are key in transmitting extracellular stimuli into an intracellular response, within the oral cavity but also in extraoral tissues. Their expression in the bone marrow (BM)-derived cells suggests their involvement in sensing the BM microenvironmental fluctuation. In the present study, we demonstrated that umbilical cord blood (UCB)-derived CD34⁺ cells express fully functional TAS2Rs along with the signal transduction cascade components and their activation by the prototypical agonist, denatonium benzoate, significantly modulated genes involved in stemness maintenance and regulation of cell trafficking. The activation of these specific pathways was confirmed in functional in vitro experiments. Denatonium exposure exerted an antiproliferative effect on UCB-derived CD34⁺ cells, mainly affecting the most undifferentiated progenitor frequency. It also reduced their clonogenicity and repopulating potential in vitro. In addition, the TAS2R signaling activation impaired the UCB-derived CD34⁺ cell trafficking, mainly reducing the migration toward the chemoattractant agent CXCL12 and modulating the expression of the adhesion molecules CD62L, CD49d, and CD29. In conclusion, our results in UCB-derived CD34⁺ cells expand the observation of TAS2R expression in the setting of BM-resident cells and shed light on the role of TAS2Rs in the extrinsic regulation of hematopoietic stem cell functions.

Extracellular ATP released from dying cells, including tumor cells, is a key mediator of inflammation and tolerance by binding to purinergic receptors on dendritic cells (DCs), resulting in inflammasome activation (via P2X7R), DC maturation (via P2Y11R), and indoleamine-2,3-dioxygenase 1 upregulation. However, the regulation of ATP-driven Indoleamine-2,3-dioxygenase 1 expression in human DCs has been poorly investigated. In this work, we aimed to investigate the ATP-driven molecular regulation of indoleamine-2,3-dioxygenase 1 expression via purinergic receptors and to provide an in-depth characterization of ATP-driven T regulatory cells induced by indoleamine-2,3-dioxygenase 1-expressing DCs. We identified P2Y11R as being responsible for ATP-driven indoleamine-2,3-dioxygenase 1 upregulation, and noncanonical NF-kB as a molecular pathway associated with ATP-dependent indoleamine-2,3-dioxygenase 1 induction through P2Y11R. Then, we investigated—but did not confirm—an involvement of inflammasome machinery through P2X7R in indoleamine-2,3-dioxygenase 1 upregulation. Finally, we evaluated the role of ATP catabolism via ATP ectonucleotidases, i.e. CD39 and CD73 and its main product adenosine, in regulating the generation of indoleamine-2,3-dioxygenase 1-driven T regulatory cells. We found that ATP-driven indoleamine-2,3-dioxygenase 1 upregulation is associated with CD73 upregulation and adenosine production. Additionally, ATP-treated indoleamine-2,3-dioxygenase 1-positive mature DCs induce PD-1-expressing bona fide suppressive T regulatory cells via adenosine A2AR. Collectively, a more in-depth understanding of ATP-driven immune-regulatory mechanisms through indoleamine-2,3-dioxygenase 1 regulation in human DCs leading to the induction of T regulatory cells can have clinical implications for the development of indoleamine-2,3-dioxygenase 1 inhibitors in cancer patients, especially in combination with immunotherapy such as an anti-CD73 or adenosine receptor agonist and immunogenic chemotherapy.

Corrigendum: Denatonium as a Bitter Taste Receptor Agonist Modifies Transcriptomic Profile and Functions of Acute Myeloid Leukemia Cells