Roe Jae-Seok, Mercan Fatih, Rivera Keith, Pappin Darryl J, Vakoc Christopher R
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
Mol Cell. 2015 Jun 18;58(6):1028-39. doi: 10.1016/j.molcel.2015.04.011. Epub 2015 May 14.
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.
含溴结构域和额外末端（BET）蛋白BRD4是白血病中已得到验证的药物靶点，但其在该疾病中的调节功能尚未完全明确。在此，我们表明，急性髓系白血病中BRD4在染色质上的占据情况与造血转录因子（TFs）PU.1、FLI1、ERG、C/EBPα、C/EBPβ和MYB在核小体缺失的增强子和启动子区域密切相关。我们提供的证据表明，这些转录因子与p300/CBP的赖氨酸乙酰转移酶活性共同作用，促进BRD4募集到它们所占据的位点以促进转录激活。研究发现，化学抑制BET溴结构域可抑制每个造血转录因子的功能输出，从而干扰该疾病中重要的谱系特异性转录回路。这些发现揭示了一种基于染色质的信号级联反应，该反应由造血转录因子、p300/CBP和BRD4组成，支持白血病维持，并且可被BET溴结构域抑制所阻断。
