Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 23, Issue 7, Pages 673-681Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.3249
Keywords
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Funding
- Leukaemia Foundation Australia
- Victoria Cancer Agency
- Senior Leukaemia Foundation Australia Fellowship
- VESKI Innovation Fellowship
- National Health and Medical Research Council of Australia [1066545, 1085015, 1106444]
- Structural Genomics Consortium
- AbbVie [1097737]
- Bayer [1097737]
- Lilly Canada [1097737]
- Novartis Research Foundation [1097737]
- Ontario Ministry of Economic Development and Innovation [1097737]
- Pfizer [1097737]
- Takeda [1097737]
- Wellcome Trust [1097737, 092809/Z/10/Z]
- Boehringer Ingelheim [1097737]
- Genome Canada through the Ontario Genomics Institute [1097737, OGI-055]
- GlaxoSmithKline [1097737]
- National Health and Medical Research Council of Australia [1066545, 1085015, 1106444] Funding Source: NHMRC
- Cancer Research UK [17001, 12475, 10827] Funding Source: researchfish
- Medical Research Council [MR/M010392/1, MC_PC_12009] Funding Source: researchfish
- Worldwide Cancer Research [14-1069] Funding Source: researchfish
- MRC [MR/M010392/1] Funding Source: UKRI
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Targeted therapies against disruptor of telomeric silencing 1-like (DOT1 L) and bromodomain-containing protein 4 (BRD4) are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1 L regulate leukemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation, we found that native BRD4 and DOT1 L exist in separate protein complexes. Genetic disruption or small-molecule inhibition of BRD4 and DOT1 L 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. DOT1 L, 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.
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