Functional interdependence of BRD4 and DOT1L in MLL leukemia
Details
Publication Year 2016-06-13, Volume 23, Issue #7, Page 673-681
Journal Title
Nature Structural & Molecular Biology
Publication Type
Journal Article
Abstract
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.
Publisher
NPG
WEHI Research Division(s)
Molecular Medicine
PubMed ID
27294782
Publisher's Version
https://doi.org/10.1038/nsmb.3249
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2016-06-17 03:01:35
Last Modified: 2018-07-11 09:37:24
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