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

Jae Seok Roe; Fatih Mercan; Keith Rivera; Darryl J. Pappin; Christopher R. Vakoc

doi:10.1016/j.molcel.2015.04.011

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

Jae Seok Roe, Fatih Mercan, Keith Rivera, Darryl J. Pappin, Christopher R. Vakoc

Department of Biochemistry

Research output: Contribution to journal › Article › peer-review

236 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1028-1039
Number of pages	12
Journal	Molecular Cell
Volume	58
Issue number	6
DOIs	https://doi.org/10.1016/j.molcel.2015.04.011
Publication status	Published - 2015 Jun 18

Bibliographical note

Funding Information:
We thank Oliver Tam and Molly Hammell from the CSHL Bioinformatics Shared Resource for assistance with the analysis of deep sequencing data. We thank Cheng-Ming Chiang for providing BRD4 and p53 expression plasmids, and James Bradner and Jun Qi for providing JQ1. This work was supported by Cold Spring Harbor Laboratory NCI Cancer Center Support grant CA455087 for developmental funds and shared resource support. Additional funding was provided by the Alex’s Lemonade Stand Foundation and the V Foundation. C.R.V. is supported by a Burroughs Wellcome Fund Career Award and NIH grant NCI RO1 CA174793. F.M. is supported by a NYS postdoctoral training program grant. J.-S.R. is supported by the Martin Sass Foundation and the Lauri Strauss Leukemia Foundation.

Publisher Copyright:
© 2015 Elsevier Inc.

All Science Journal Classification (ASJC) codes

Molecular Biology
Cell Biology

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10.1016/j.molcel.2015.04.011

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title = "BET Bromodomain Inhibition Suppresses the Function of Hematopoietic Transcription Factors in Acute Myeloid Leukemia",

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.",

author = "Roe, {Jae Seok} and Fatih Mercan and Keith Rivera and Pappin, {Darryl J.} and Vakoc, {Christopher R.}",

note = "Funding Information: We thank Oliver Tam and Molly Hammell from the CSHL Bioinformatics Shared Resource for assistance with the analysis of deep sequencing data. We thank Cheng-Ming Chiang for providing BRD4 and p53 expression plasmids, and James Bradner and Jun Qi for providing JQ1. This work was supported by Cold Spring Harbor Laboratory NCI Cancer Center Support grant CA455087 for developmental funds and shared resource support. Additional funding was provided by the Alex{\textquoteright}s Lemonade Stand Foundation and the V Foundation. C.R.V. is supported by a Burroughs Wellcome Fund Career Award and NIH grant NCI RO1 CA174793. F.M. is supported by a NYS postdoctoral training program grant. J.-S.R. is supported by the Martin Sass Foundation and the Lauri Strauss Leukemia Foundation. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

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N2 - 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.

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

Abstract

Bibliographical note

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