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

被引：274

作者：

Roe, Jae-Seok ^{[1
]}

Mercan, Fatih ^{[1
]}

Rivera, Keith ^{[1
]}

Pappin, Darryl J. ^{[1
]}

Vakoc, Christopher R. ^{[1
]}

机构：

[1] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA

来源：

MOLECULAR CELL | 2015年 / 58卷 / 06期

关键词：

CREB-BINDING PROTEIN; IN-VIVO; SELECTIVE-INHIBITION; C/EBP-ALPHA; P-TEFB; C-MYC; BRD4; CHROMATIN; ACETYLATION; RECRUITMENT;

D O I：

10.1016/j.molcel.2015.04.011

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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/EBP alpha, C/EBP beta, 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.

引用

页码：1028 / 1039

页数：12

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