BET Bromodomain Inhibition Suppresses the Function of Hematopoietic Transcription Factors in Acute Myeloid Leukemia.
Mol Cell
; 58(6): 1028-39, 2015 Jun 18.
Article
em En
| MEDLINE
| ID: mdl-25982114
ABSTRACT
The bromodomain and extraterminal (BET) protein BRD4 is a validated drug target in leukemia, yet its regulatory function in this disease is not well understood. Here, we show that BRD4 chromatin occupancy in acute myeloid leukemia closely correlates with the hematopoietic transcription factors (TFs) PU.1, FLI1, ERG, C/EBPα, C/EBPß, and MYB at nucleosome-depleted enhancer and promoter regions. We provide evidence that these TFs, in conjunction with the lysine acetyltransferase activity of p300/CBP, facilitate BRD4 recruitment to their occupied sites to promote transcriptional activation. Chemical inhibition of BET bromodomains was found to suppress the functional output of each hematopoietic TF, thereby interfering with essential lineage-specific transcriptional circuits in this disease. These findings reveal a chromatin-based signaling cascade comprised of hematopoietic TFs, p300/CBP, and BRD4 that supports leukemia maintenance and is suppressed by BET bromodomain inhibition.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
/
Proteínas Nucleares
/
Sistema Hematopoético
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Estados Unidos