| Literature DB >> 27294782 |
Omer Gilan1,2, Enid Y N Lam1,2, Isabelle Becher3, Dave Lugo4, Ester Cannizzaro5, Gerard Joberty3, Aoife Ward3, Meike Wiese5, Chun Yew Fong1,2,6, Sarah Ftouni1, Dean Tyler1,2, Kym Stanley1, Laura MacPherson1, Chen-Fang Weng1, Yih-Chih Chan1, Margherita Ghisi1, David Smil7, Christopher Carpenter8, Peter Brown7, Neil Garton4, Marnie E Blewitt9,10, Andrew J Bannister5, Tony Kouzarides5, Brian J P Huntly11,12, Ricky W Johnstone1,2, Gerard Drewes3, Sarah-Jane Dawson1,2,13, Cheryl H Arrowsmith7,14, Paola Grandi3, Rab K Prinjha4, Mark A Dawson1,2,6,13.
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.Entities:
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Year: 2016 PMID： 27294782 DOI： 10.1038/nsmb.3249
Source DB: PubMed Journal: Nat Struct Mol Biol ISSN： 1545-9985 Impact factor: 15.369