Functional interdependence of BRD4 and DOT1L in MLL leukemia.
Nature Structural and Molecular Biology
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Gilan, O., Lam, E., Becher, I., Lugo, D., Cannizzaro, E., Joberty, G., Ward, A., et al. (2016). Functional interdependence of BRD4 and DOT1L in MLL leukemia.. Nature Structural and Molecular Biology, 23 (7), 673-681. https://doi.org/10.1038/nsmb.3249
Targeted therapies against disruptor of telomeric silencing 1-like (DOT1L) and bromodomain-containing protein 4 (BRD4) are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation, we found that native BRD4 and DOT1L exist in separate protein complexes. Genetic disruption or small-molecule inhibition of BRD4 and DOT1L showed marked synergistic activity against MLL leukemia cell lines, primary human leukemia cells and mouse leukemia models. Mechanistically, we found a previously unrecognized functional collaboration between DOT1L and BRD4 that is especially important at highly transcribed genes in proximity to superenhancers. DOT1L, via dimethylated histone H3 K79, facilitates histone H4 acetylation, which in turn regulates the binding of BRD4 to chromatin. These data provide new insights into the regulation of transcription and specify a molecular framework for therapeutic intervention in this disease with poor prognosis.
Medical Research Council (MR/M010392/1)
ECH2020 EUROPEAN RESEARCH COUNCIL (ERC) (647685)
Worldwide Cancer Research (14-1069)
External DOI: https://doi.org/10.1038/nsmb.3249
This record's URL: https://www.repository.cam.ac.uk/handle/1810/297257
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