GRK2 AND HISTAMINE H2 RECEPTOR AS MOLECULAR TARGETS FOR ACUTE MYELOID LEUKEMIA

GISELA GOMEZ; EMILIANA ECHEVERRÍA; ANA SAHORES; MAXIMILIANO DE SOUSA; CARLOS DAVIO; NATALIA FERNANDEZ; CARINA SHAYO

Mar del Plata

Congreso; LXVIII REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA; 2023

SAIC

Previously we demonstrated that increases in intracellular cAMP play an important role in acute myeloid leukemia (AML) cell proliferation/differentiation. In this regard, histamine (Hist), through H2 receptor (H2R), rises cAMP levels but fails to promote cell differentiation due to the rapid H2R desensitization (DES) mediated by GRK2. Structurally, GRKs possess an RGS-homology domain (RH) responsible for G-protein activity regulation, a kinase domain engaged in receptor phosphorylation, and a region responsible for membrane localization. Through a docking-based strategy, we identified inhibitors of the RH domain of GRK2 with the ability to interfere with RH actions. The aim of this study was to evaluate the effect of combining Hist treatment with GRK2 inhibitors targeting different domains, on the proliferation of AML cell models. We selected compounds that inhibit RH activity towards Gαs-GPCRs (C3 and C5) or Gαq (C5 and C13) in the screening model, and CMPD as a commercially available GRK2-kinase inhibitor. First, we assessed U937 and HL60 cell proliferation after 72h treatment with 100µM Hist and different concentrations of GRK2 inhibitors, either by cell count or by using Incucyte® cell imaging. We detected a concentration-dependent anti-proliferative effect of C3, C5, and CMPD, with Hist enhancing C3 and CMPD effect (p