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Nat Struct Mol Biol. 2016 Jul;23(7):673-81. doi: 10.1038/nsmb.3249. Epub 2016 Jun 13.

Functional interdependence of BRD4 and DOT1L in MLL leukemia.

Author information

1
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
2
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
3
Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Heidelberg, Germany.
4
Epinova DPU, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Stevenage, UK.
5
The Gurdon Institute, University of Cambridge, Cambridge, UK.
6
Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
7
Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
8
Cancer Epigenetics DPU, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
9
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
10
Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
11
Department of Haematology, Cambridge Institute for Medical Research, Cambridge, UK.
12
Cambridge Stem Cell Institute, Cambridge, UK.
13
Centre for Cancer Research, University of Melbourne, Melbourne, Victoria, Australia.
14
Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

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.

PMID:
27294782
DOI:
10.1038/nsmb.3249
[Indexed for MEDLINE]

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