Please use this identifier to cite or link to this item:
Type: Artigo
Title: BRD4 inhibition enhances azacitidine efficacy in acute myeloid leukemia and myelodysplastic syndromes
Author: Pericole, Fernando Vieira
Lazarini, Mariana
de Paiva, Luciana Bueno
Santos Duarte, Adriana da Silva
Vieira Ferro, Karla Priscila
Niemann, Fernanda Soares
Roversi, Fernanda Marconi
Olalla Saad, Sara Teresinha
Abstract: Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell-based disorders characterized by ineffective hematopoiesis, increased genomic instability and a tendency to progress toward acute myeloid leukemia (AML). MDS and AML cells present genetic and epigenetic abnormalities and, due to the heterogeneity of thesemolecular alterations, the current treatment options remain unsatisfactory. Hypomethylating agents (HMA), especially azacitidine, are the mainstay of treatment for high-risk MDS patients and HMA are used in treating elderly AML. The aim of this study was to investigate the potential role of the epigenetic reader bromodomain-containing protein-4 (BRD4) in MDS and AML patients. We identified the upregulation of the short variant BRD4 in MDS and AML patients, which was associated with a worse outcome of MDS. Furthermore, the inhibition of BRD4 in vitro with JQ1 or shRNA induced leukemia cell apoptosis, especially when combined to azacitidine, and triggered the activation of the DNA damage response pathway. JQ1 and AZD6738 (a specific ATR inhibitor) also synergized to induce apoptosis in leukemia cells. Our results indicate that the BRD4-dependent transcriptional program is a defective pathway in MDS and AML pathogenesis and its inhibition induces apoptosis of leukemia cells, which is enhanced in combination with HMA or an ATR inhibitor
Subject: Síndromes mielodisplásicas
Leucemia mielóide aguda
Country: Suiça
Editor: Frontiers Research Foundation
Rights: aberto
Identifier DOI: 10.3389/fonc.2019.00016
Date Issue: 2019
Appears in Collections:FCM - Artigos e Outros Documentos
HEMO - Artigos e Outros Documentos

Files in This Item:
File Description SizeFormat 
000457084000001.pdf2.3 MBAdobe PDFView/Open

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.