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.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation / drug effects
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Acute Disease
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Animals
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Azepines / pharmacology
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Blotting, Western
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CCAAT-Enhancer-Binding Protein-beta / genetics
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CCAAT-Enhancer-Binding Protein-beta / metabolism
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Cell Line, Tumor
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Gene Expression Profiling
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Hematopoietic System / metabolism*
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Histones / metabolism
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Humans
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Leukemia, Myeloid / genetics
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Leukemia, Myeloid / metabolism
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Leukemia, Myeloid / pathology
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Mice
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NIH 3T3 Cells
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism
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Protein Binding / drug effects
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Proto-Oncogene Protein c-fli-1 / genetics
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Proto-Oncogene Protein c-fli-1 / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-myb / genetics
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Proto-Oncogene Proteins c-myb / metabolism
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcriptional Regulator ERG
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Triazoles / pharmacology
Substances
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(+)-JQ1 compound
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Azepines
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Brd4 protein, mouse
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CCAAT-Enhancer-Binding Protein-beta
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ERG protein, mouse
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Fli1 protein, mouse
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Histones
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Nuclear Proteins
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Oncogene Proteins
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Proto-Oncogene Protein c-fli-1
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-myb
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Trans-Activators
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Transcription Factors
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Transcriptional Regulator ERG
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Triazoles
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proto-oncogene protein Spi-1
Associated data
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GEO/GSE66068
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GEO/GSE66122
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GEO/GSE66123