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13.06.16 Identifying therapeutic targets in MLL among proteins that regulate gene transcription

last modified Jun 21, 2016 05:47 PM
The Kouzarides lab is working with lab alumnus Mark Dawson in Australia to identify therapeutic targets in the aggressive disease Mixed-Lineage Leukaemia. They report that DOT1L works with known target BRD4 to regulate transcription of key genes.
13.06.16 Identifying therapeutic targets in MLL among proteins that regulate gene transcription

Extract of Fig.4b from the paper: A subset of genes is responsive to inhibition of both BRD4 and DOT1L

Functional interdependence of BRD4 and DOT1L in MLL leukemia

Gilan O et al. (2016) Nat Struct Mol Biol. doi: 10.1038/nsmb.3249. [Epub ahead of print]  PMID: 27294782

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.

 

More about the Kouzarides lab.

Studying development to understand disease

The Gurdon Institute is funded by the Wellcome Trust and Cancer Research UK to study the biology of development, and how normal growth and maintenance go wrong in cancer and other diseases.