| Literature DB >> 25982114 |
Jae-Seok Roe1, Fatih Mercan1, Keith Rivera1, Darryl J Pappin1, Christopher R Vakoc2.
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/EBPβ, 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.Entities:
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Year: 2015 PMID： 25982114 PMCID： PMC4475489 DOI： 10.1016/j.molcel.2015.04.011
Source DB: PubMed Journal: Mol Cell ISSN： 1097-2765 Impact factor: 17.970