RELEVANCE OF GLUCOCORTICOID RECEPTOR IN ACUTE MYELOID LEUKEMIA

JULIÁN MARTÍNEZ MAYER; LUCIANA ROCHA VIEGAS; ADALI PECCI; MICAELA SILBERMINS

Congreso; LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2019

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults, and is characterized by accumulation of immature white blood cells with aberrant proliferation and differentiation blockade. One type of AML is Acute Promyelocytic Leukemia (APL), distinguished by the expression of promyelocytic leukemia (PML)-retinoic acid receptor (RAR) chimeric protein that acts as an antagonist of wild-type RAR. Treatment of APL patients with retinoic acid (RA) promotes at least partial transcriptional de-repression, but unfortunately provides transient clinical remission. Interestingly, we observed that APL-NB4 cell treatment with RA and glucocorticoids markedly enhances cell differentiation (D) and potentiates expression of RARtarget genes. Thus, we hypothesize that glucocorticoid receptor (GR) localization and target gene regulation in undifferentiated (U) cells somehow determine its subsequent interaction and functional effects along the myeloid differentiation program. Therefore, in our aim to elucidate GR relevance in U and D cells, we report here that a different nuclear GR distribution is observed in western blots depending on the leukemic context (AML or APL) of cells grown either in full (F) or steroid-deprived (CS) serum-containing medium for 24h. Moreover, by RT-qPCR assays we quantified TTP (U-F: 0.33±0.20, U-CS: 0.39±0.17, D-F: 1.04±0.29, D-CS: 0.82±0.10) and DUSP-1 mRNA levels (U-F: 0.96±0.32, U-CS: 0.63±0.14, D-F: 0.57 ±0.10, D-CS: 0.90±0.36), resulting both in induced expression levels in D-cells, regardless of serum conditions or in CS-serum, respectively. Furthermore, co-IP experiments reveal a novel GR-RARα complex in U-NB4 nuclei, which becomes enhanced in D-cells. Collectively these data lead us to suggest that depending on the differentiation context, steroids may present opposing regulatory effects. Further characterization of this molecular context could aid to identify attractive targets for therapeutic strategies in myeloid leukemia.