BRD4 Inhibition Enhances Azacitidine Efficacy in Acute Myeloid Leukemia and Myelodysplastic Syndromes
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...
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doaj-58adf68892d54164ad581714d9b904452020-11-24T21:40:16ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2019-01-01910.3389/fonc.2019.00016429097BRD4 Inhibition Enhances Azacitidine Efficacy in Acute Myeloid Leukemia and Myelodysplastic SyndromesFernando Vieira Pericole0Mariana Lazarini1Mariana Lazarini2Luciana Bueno de Paiva3Adriana da Silva Santos Duarte4Karla Priscila Vieira Ferro5Fernanda Soares Niemann6Fernanda Marconi Roversi7Fernanda Marconi Roversi8Sara Teresinha Olalla Saad9Hematology and Transfusion Medicine Center, Instituto Nacional de Ciência e Tecnologia do Sangue, University of Campinas, Hemocentro-Unicamp, São Paulo, BrazilHematology and Transfusion Medicine Center, Instituto Nacional de Ciência e Tecnologia do Sangue, University of Campinas, Hemocentro-Unicamp, São Paulo, BrazilDepartment of Pharmaceutical Sciences, Federal University of São Paulo, São Paulo, BrazilHematology and Transfusion Medicine Center, Instituto Nacional de Ciência e Tecnologia do Sangue, University of Campinas, Hemocentro-Unicamp, São Paulo, BrazilHematology and Transfusion Medicine Center, Instituto Nacional de Ciência e Tecnologia do Sangue, University of Campinas, Hemocentro-Unicamp, São Paulo, BrazilHematology and Transfusion Medicine Center, Instituto Nacional de Ciência e Tecnologia do Sangue, University of Campinas, Hemocentro-Unicamp, São Paulo, BrazilHematology and Transfusion Medicine Center, Instituto Nacional de Ciência e Tecnologia do Sangue, University of Campinas, Hemocentro-Unicamp, São Paulo, BrazilHematology and Transfusion Medicine Center, Instituto Nacional de Ciência e Tecnologia do Sangue, University of Campinas, Hemocentro-Unicamp, São Paulo, BrazilUniversidade São Francisco (USF), Bragança Paulista, São Paulo, BrazilHematology and Transfusion Medicine Center, Instituto Nacional de Ciência e Tecnologia do Sangue, University of Campinas, Hemocentro-Unicamp, São Paulo, BrazilMyelodysplastic 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 these molecular 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.https://www.frontiersin.org/article/10.3389/fonc.2019.00016/fullmyelodysplastic syndromesacute myeloid leukemiaBET member of bromodomain-containing proteinsazacitidineAZD6738 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Fernando Vieira Pericole Mariana Lazarini Mariana Lazarini Luciana Bueno de Paiva Adriana da Silva Santos Duarte Karla Priscila Vieira Ferro Fernanda Soares Niemann Fernanda Marconi Roversi Fernanda Marconi Roversi Sara Teresinha Olalla Saad |
spellingShingle |
Fernando Vieira Pericole Mariana Lazarini Mariana Lazarini Luciana Bueno de Paiva Adriana da Silva Santos Duarte Karla Priscila Vieira Ferro Fernanda Soares Niemann Fernanda Marconi Roversi Fernanda Marconi Roversi Sara Teresinha Olalla Saad BRD4 Inhibition Enhances Azacitidine Efficacy in Acute Myeloid Leukemia and Myelodysplastic Syndromes Frontiers in Oncology myelodysplastic syndromes acute myeloid leukemia BET member of bromodomain-containing proteins azacitidine AZD6738 |
author_facet |
Fernando Vieira Pericole Mariana Lazarini Mariana Lazarini Luciana Bueno de Paiva Adriana da Silva Santos Duarte Karla Priscila Vieira Ferro Fernanda Soares Niemann Fernanda Marconi Roversi Fernanda Marconi Roversi Sara Teresinha Olalla Saad |
author_sort |
Fernando Vieira Pericole |
title |
BRD4 Inhibition Enhances Azacitidine Efficacy in Acute Myeloid Leukemia and Myelodysplastic Syndromes |
title_short |
BRD4 Inhibition Enhances Azacitidine Efficacy in Acute Myeloid Leukemia and Myelodysplastic Syndromes |
title_full |
BRD4 Inhibition Enhances Azacitidine Efficacy in Acute Myeloid Leukemia and Myelodysplastic Syndromes |
title_fullStr |
BRD4 Inhibition Enhances Azacitidine Efficacy in Acute Myeloid Leukemia and Myelodysplastic Syndromes |
title_full_unstemmed |
BRD4 Inhibition Enhances Azacitidine Efficacy in Acute Myeloid Leukemia and Myelodysplastic Syndromes |
title_sort |
brd4 inhibition enhances azacitidine efficacy in acute myeloid leukemia and myelodysplastic syndromes |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Oncology |
issn |
2234-943X |
publishDate |
2019-01-01 |
description |
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 these molecular 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. |
topic |
myelodysplastic syndromes acute myeloid leukemia BET member of bromodomain-containing proteins azacitidine AZD6738 |
url |
https://www.frontiersin.org/article/10.3389/fonc.2019.00016/full |
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