COOPERATION BETWEEN GLUCOCORTICOID AND RETINOIC ACID RECEPTORS ON TRANSCRIP- TIONAL REGULATION ENHANCES DIFFERENTIATION IN ACUTE MYELOID LEUKEMIA

MICAELA SILBERMINS; EVELYN OLSZANOWSKI; MATT TEATER; CEM MEYDAN; CIHANGIR DUY; ADALI PECCI; ARI MELNICK; LUCIANA ROCHA VIEGAS

Congreso; Reunión Conjunta de Sociedades de Biociencias 2021; 2021

SAIC. SAI. AAFE. NANOMED-AR

In Acute Promyelocytic Leukemia (APL) cell differentiation is arrested and retinoic acid (RA) therapy alone ends in relapse. Our previous results showed that the glucocorticoid dexamethasone (DEX) significantly enhances RA-induced myeloid differentiation. APL-NB4 cells were treated with RA 0.1 μM in the presence or absence of DEX 0.5 μM and RNAseq analysis was performed. Differential gene expression (FC>1.5, p-adj<0.05, LR>10) between hormone-treated and control (CTRL) samples from three biological replicates was calculated with DESeq2. From a total of 6983 regulated genes, 6244 were regulated by RA+DEX, 5610 by RA and 204 by DEX. Most up (2479) and down-regulated genes (2322) between RA and RA+DEX samples are shared. Gene Set Enrichment Analysis (GSEA) revealed that expression of genes associated with myeloid development (FDR q-val<1E-6) and hematopoietic stemness inhibition (FDR q-val<1E-6) signatures was markedly enhanced upon addition of DEX. Some of the 565 RA+DEX-potentiated and induced genes (RA+DEXup) are AIM2, FOS and TLR6. Concomitantly, peaks obtained from Transposase-Accessible Chromatin (ATAC)-seq analysis were associated to genes using ChIPpeakAnno, within 1mb from TSS. RA/RA+DEX induced differential peaks, compared to CTRL, in 491 RA+DEXup genes, while only 53 of them were associated with regulated peaks due to addition of DEX. Moreover, 40.7% (200/491) of these genes have a peak in the promoter, whether differential or not, and at least one differential peak in the distal region. These distal regions are enriched for glucocorticoid receptor response elements. Furthermore, this 200 gene subset is responsible for the enrichment of GSEA signatures myeloid development (p-val<6E-15) and hematopoietic stemness inhibition (p-val<2E-16). Taken together, these results suggest that DEX has little effect in chromatin accessibility and may regulate transcription on RA-mediated accessible regions during NB4 cell differentiation.