BET Bromodomain Inhibition Suppresses the Function of Hematopoietic Transcription Factors in Acute Myeloid Leukemia

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)...

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Bibliographic Details
Published in:Molecular cell 2015-06, Vol.58 (6), p.1028-1039
Main Authors: Roe, Jae-Seok, Mercan, Fatih, Rivera, Keith, Pappin, Darryl J., Vakoc, Christopher R.
Format: Article
Language:English
Subjects:
Acetylation - drug effects
Acute Disease
Animals
Azepines - pharmacology
Blotting, Western
CCAAT-Enhancer-Binding Protein-beta - genetics
CCAAT-Enhancer-Binding Protein-beta - metabolism
Cell Line, Tumor
Gene Expression Profiling
Hematopoietic System - metabolism
Histones - metabolism
Humans
Leukemia, Myeloid - genetics
Leukemia, Myeloid - metabolism
Leukemia, Myeloid - pathology
Mice
NIH 3T3 Cells
Nuclear Proteins - antagonists & inhibitors
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Oncogene Proteins - genetics
Oncogene Proteins - metabolism
Protein Binding - drug effects
Proto-Oncogene Protein c-fli-1 - genetics
Proto-Oncogene Protein c-fli-1 - metabolism
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-myb - genetics
Proto-Oncogene Proteins c-myb - metabolism
Reverse Transcriptase Polymerase Chain Reaction
RNA Interference
Trans-Activators - genetics
Trans-Activators - metabolism
Transcription Factors - antagonists & inhibitors
Transcription Factors - genetics
Transcription Factors - metabolism
Transcriptional Regulator ERG
Triazoles - pharmacology
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Summary: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. [Display omitted] •BRD4 occupancy in leukemia correlates with hematopoietic transcription factors•The p300/CBP lysine acetyltransferases are essential for global BRD4 recruitment•p300 acetylates ERG to promote an interaction with BRD4•Hematopoietic transcription factors are functionally suppressed by BET inhibitors BET inhibitors are currently under clinical investigation as epigenetic therapy in leukemia. Roe et al. identify a molecular mechanism that can account for the context-dependent transcriptional effects of these agents. They show that the BET protein BRD4 is required for the functional output of an ensemble of lineage-specific transcription factors.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2015.04.011