Super-enhancers (SEs), which are composed of large clusters of enhancers densely 
loaded with the Mediator complex, transcription factors and chromatin 
regulators, drive high expression of genes implicated in cell identity and 
disease, such as lineage-controlling transcription factors and oncogenes. BRD4 
and CDK7 are positive regulators of SE-mediated transcription. By contrast, 
negative regulators of SE-associated genes have not been well described. Here we 
show that the Mediator-associated kinases cyclin-dependent kinase 8 (CDK8) and 
CDK19 restrain increased activation of key SE-associated genes in acute myeloid 
leukaemia (AML) cells. We report that the natural product cortistatin A (CA) 
selectively inhibits Mediator kinases, has anti-leukaemic activity in vitro and 
in vivo, and disproportionately induces upregulation of SE-associated genes in 
CA-sensitive AML cell lines but not in CA-insensitive cell lines. In AML cells, 
CA upregulated SE-associated genes with tumour suppressor and 
lineage-controlling functions, including the transcription factors CEBPA, IRF8, 
IRF1 and ETV6 (refs 6-8). The BRD4 inhibitor I-BET151 downregulated these 
SE-associated genes, yet also has anti-leukaemic activity. Individually 
increasing or decreasing the expression of these transcription factors 
suppressed AML cell growth, providing evidence that leukaemia cells are 
sensitive to the dosage of SE-associated genes. Our results demonstrate that 
Mediator kinases can negatively regulate SE-associated gene expression in 
specific cell types, and can be pharmacologically targeted as a therapeutic 
approach to AML.