DIFFERENTIATION THERAPY IN ACUTE MYELOID LEUKEMIA.H2 HISTAMINE RECEPTOR AND MRP4/ABCC4AS MOLECULAR TARGETS.

RODRIGUEZ, ANGELA; DAVIO, CARLOS; DIEZ, FEDERICO; DÍAZ NEBREDA, ANTONELA; SHAYO, CARINA

Capital Federal

Congreso; XVIII Jornadas Anuales Multidisciplinarias; 2016

Sociedad Argentina de Biología

Acute myeloid leukemia (AML) is a heterogeneous clonal disorder where early hematopoietic cells fail to differentiate and do not undergo programmed cell death or apoptosis. Over the last few decades, the concept of differentiation therapy aroused considerable interest. Previously we reported that increment in intracellular cAMP levels by the modulation of different proteins involved in its metabolism, namely the histamine H2 receptor (H2R) (cAMP production), phosphodiesterases (PDE) (cAMP degradation); and MRP4 (cAMP efflux) play an important role in leukemic cell differentiation. Here, we evaluated in human promonocytic leukemia U937 cells the regulation of MRP4 expression by H2R, and the impact of extracellular cAMP on leukemic cell proliferation. We show that H2R stimulation induced an increase in MRP4 mRNA and protein expression. Likewise, U937 cells stably overexpressing H2R (B10 clone) revealed higher levels of MRP4 than U937 cells, which correlate with higher cAMP intracellular levels. As well, the increment of MRP4 levels induced by H2R stimulation in B10 cells was significantly higher than in U937 cells. To determine the effect of extracellular cAMP on U937 cell proliferation, [3H]Thymidine assays were performed in the presence of different cAMP concentration. Our results show a concentration-dependent increment in cell proliferation, indicating that extracellular cAMP levels play an important role in U937 cell proliferation. Altogether, the results provide new data about cAMP role in leukemic cell proliferation and support that polypharmacological differentiation strategy with H2R agonist and MRP4 inhibitors would be beneficial to avoid possible resistance.