Discovery and Characterization of Super-Enhancer Associated Dependencies in Diffuse Large B-Cell Lymphoma

By B. Chapuy, Michael R Mckeown, Charles Y. Lin, Stefano Monti, M. Roemer, J. Qi, P. Rahl, Heather H. Sun, Kelly T. Yeda, John G Doench and 6 more. Cancer Cell, 2013

694 citations recorded by the source corpus.

Summary Diffuse Large B-Cell Lymphoma (DLBCL) is a biologically heterogeneous and clinically aggressive disease. Here, we explore the role of BET bromodomain proteins in DLBCL, using integrative chemical genetics and functional epigenomics. We observe highly asymmetric loading of BRD4 at enhancers, with approximately 33% of all BRD4 localizing to enhancers at 1.6% of occupied genes. These super-enhancers prove particularly sensitive to bromodomain inhibition, explaining the selective effect of BET inhibitors on oncogenic and lineage-specific transcriptional circuits. Functional study of genes marked by super-enhancers identifies DLBCLs dependent on OCA-B and suggests a strategy for discovering unrecognized cancer dependencies. Translational studies performed on a comprehensive panel of DLBCLs establish a therapeutic rationale for evaluating BET inhibitors in this disease.

Subfields: Molecular Biology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/405fd6d90bc078ceb782e5f3b06685b81aa686f3

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Citations in the corpus

The role of mutations in epigenetic regulators in myeloid malignancies (2012, background): “Studies of cohesin dynamics upon BRD4 inhibition with JQ1 led to a twofold decrease in cohesin occupancy at super-enhancer sites and decreased oncogene expression (102, 103).”
dbSUPER: a database of super-enhancers in mouse and human genome (2015, methodology): “The above mentioned studies have generated large amount of data by profiling ChIP-seq signal for Mediator complex (Med1), master transcription factors (MyoD, T-bet and C/EBPα) (15), H3K27ac (17, 24, 29), BRD4 (16, 24) and p300 (35) in different tissue and cell types.”
Coactivator condensation at super-enhancers links phase separation and gene control (2018, background): “The enhancer clusters that make up SEs are occupied by master TFs and unusually high densities of factors, including BRD4 and MED1, that are coactivators (31–35) whose presence can be used to define SEs (14, 15, 21).”
Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. (2015, background): “Chemistry & Biology 22, in regulating their expressions (Chapuy et al., 2013; Loven et al., 2013).”
Targeting transcription regulation in cancer with a covalent CDK7 inhibitor (2014, background): “Tumor cell oncogenes can acquire super-enhancers, which drive high-level expression yet can be especially sensitive to perturbation 25–28 .”
Transcriptional Addiction in Cancer (2017, positive): “…TFs acquire especially large SEs, with exceptionally high densities of enhancer factors, and this may further contribute to the exceptional vulnerability of SEdriven oncogenic TFs seen with inhibition of BRD4 (Bhagwat et al., 2016; Chapuy et al., 2013; Loven et al., 2013; Shi and Vakoc, 2014).”