Functional interdependence of BRD4 and DOT1L in MLL leukemia.
Omer GilanEnid Y N LamIsabelle BecherDave LugoEster CannizzaroGerard JobertyAoife WardMeike WieseChun Yew FongSarah FtouniDean TylerKym StanleyLaura MacPhersonChen-Fang WengYih-Chih ChanMargherita GhisiDavid SmilChristopher CarpenterPeter BrownNeil GartonMarnie E BlewittAndrew J BannisterTony KouzaridesBrian J P HuntlyRicky W JohnstoneGerard DrewesSarah-Jane DawsonCheryl H ArrowsmithPaola GrandiRab K PrinjhaMark A DawsonPublished in: Nature structural & molecular biology (2016)
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.
Keyphrases
- acute myeloid leukemia
- poor prognosis
- small molecule
- energy transfer
- bone marrow
- protein protein
- clinical trial
- genome wide
- transcription factor
- long non coding rna
- randomized controlled trial
- endothelial cells
- binding protein
- induced apoptosis
- oxidative stress
- high resolution
- drug delivery
- sensitive detection
- machine learning
- cell cycle arrest
- single molecule
- phase ii
- genome wide identification
- dna repair