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BRD4 Inhibition Enhances Azacitidine Efficacy in Acute Myeloid Leukemia and Myelodysplastic Syndromes.
Pericole, Fernando Vieira; Lazarini, Mariana; de Paiva, Luciana Bueno; Duarte, Adriana da Silva Santos; Vieira Ferro, Karla Priscila; Niemann, Fernanda Soares; Roversi, Fernanda Marconi; Olalla Saad, Sara Teresinha.
Afiliação
  • Pericole FV; Hematology and Transfusion Medicine Center, Instituto Nacional de Ciência e Tecnologia do Sangue, University of Campinas, Hemocentro-Unicamp, São Paulo, Brazil.
  • Lazarini M; Hematology and Transfusion Medicine Center, Instituto Nacional de Ciência e Tecnologia do Sangue, University of Campinas, Hemocentro-Unicamp, São Paulo, Brazil.
  • de Paiva LB; Department of Pharmaceutical Sciences, Federal University of São Paulo, São Paulo, Brazil.
  • Duarte ADSS; Hematology and Transfusion Medicine Center, Instituto Nacional de Ciência e Tecnologia do Sangue, University of Campinas, Hemocentro-Unicamp, São Paulo, Brazil.
  • Vieira Ferro KP; Hematology and Transfusion Medicine Center, Instituto Nacional de Ciência e Tecnologia do Sangue, University of Campinas, Hemocentro-Unicamp, São Paulo, Brazil.
  • Niemann FS; Hematology and Transfusion Medicine Center, Instituto Nacional de Ciência e Tecnologia do Sangue, University of Campinas, Hemocentro-Unicamp, São Paulo, Brazil.
  • Roversi FM; Hematology and Transfusion Medicine Center, Instituto Nacional de Ciência e Tecnologia do Sangue, University of Campinas, Hemocentro-Unicamp, São Paulo, Brazil.
  • Olalla Saad ST; Hematology and Transfusion Medicine Center, Instituto Nacional de Ciência e Tecnologia do Sangue, University of Campinas, Hemocentro-Unicamp, São Paulo, Brazil.
Front Oncol ; 9: 16, 2019.
Article em En | MEDLINE | ID: mdl-30761268
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Front Oncol Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Brasil País de publicação: Suíça
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Front Oncol Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Brasil País de publicação: Suíça