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.
Bibliographical noteFunding 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.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology