期刊
MOLECULAR CELL
卷 58, 期 6, 页码 1028-1039出版社
CELL PRESS
DOI: 10.1016/j.molcel.2015.04.011
关键词
-
资金
- Cold Spring Harbor Laboratory NCI Cancer Center [CA455087]
- Alex's Lemonade Stand Foundation
- V Foundation
- Burroughs Wellcome Fund Career Award
- NIH [NCI RO1 CA174793]
- NYS postdoctoral training program grant
- Martin Sass Foundation
- Lauri Strauss Leukemia Foundation
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据