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

Roe, Jae-Seok, Mercan, Fatih, Rivera, Keith, Pappin, Darryl J, Vakoc, Christopher R (June 2015) BET Bromodomain Inhibition Suppresses the Function of Hematopoietic Transcription Factors in Acute Myeloid Leukemia. Molecular Cell, 58 (6). pp. 1028-1036. ISSN 1097-2765

Abstract

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.

Item Type:	Paper
Subjects:	bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > bromodomain and extraterminal protein diseases & disorders > cancer > cancer types > leukemia
CSHL Authors:	Mercan, Fatih Pappin, Darryl J. Rivera, Keith Roe, Jae Seok Vakoc, Christopher R.
Communities:	CSHL Cancer Center Program > Gene Regulation and Cell Proliferation CSHL Cancer Center Program > Signal Transduction CSHL Cancer Center Shared Resources > Bioinformatics Service CSHL Cancer Center Shared Resources > Flow Cytometry Service CSHL Cancer Center Shared Resources > Functional Genomics and Genetics Service CSHL Cancer Center Shared Resources > Mass Spectrometry Service CSHL Cancer Center Shared Resources > Proteomics Service CSHL labs > Pappin lab CSHL labs > Vakoc lab CSHL Cancer Center Shared Resources > DNA Sequencing Service
Depositing User:	Matt Covey
Date:	18 June 2015
Date Deposited:	19 May 2015 17:02
Last Modified:	05 Nov 2015 15:36
PMCID:	PMC4475489
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/31507

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