Journal article
Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia
MA Dawson, RK Prinjha, A Dittmann, G Giotopoulos, M Bantscheff, WI Chan, SC Robson, CW Chung, C Hopf, MM Savitski, C Huthmacher, E Gudgin, D Lugo, S Beinke, TD Chapman, EJ Roberts, PE Soden, KR Auger, O Mirguet, K Doehner Show all
Nature | NATURE PUBLISHING GROUP | Published : 2011
DOI: 10.1038/nature10509
Abstract
Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which are often refractory to conventional therapies. Many MLL-fusion partners are members of the super elongation complex (SEC), a critical regulator of transcriptional elongation, suggesting that aberrant control of this process has an important role in leukaemia induction. Here we use a global proteomic strategy to demonstrate that MLL fusions, as part of SEC and the polymerase-associated factor complex (PAFc), are associated with the BET family of acetyl-lysine recognizing, chromatin 'adaptor' proteins. These data provided the basis for therapeutic intervention in..
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Awarded by Wellcome Trust
Funding Acknowledgements
We thank S. J. Dawson, A. Bannister, S. Anand and all members of the Huntly and Kouzarides laboratories. We are grateful to H. Doehner, the NCRI AML trials biobank and A. Giles for the provision of patient samples. We acknowledge D. Huang for the BCL2 expression plasmid, L. Gordon for supplying fluorescence resonance energy transfer data and R. Woodward, C. Delves, E. Jones and P. Holmes for protein production. J. Witherington, N. Parr, S. Baddeley and J. Seal provided compound selectivity data. We thank N. Deeks and L. Cutler for providing sample and PK data analysis. We acknowledge K. Smitheman and A. Wyce for help with the cellular analysis of the BET inhibitors, P. Grandi for suggestions and discussion, S. Chan for biophysical assay data, and members of the Epinova team for discussion and suggestions. We thank staff at the ESRF at Grenoble for beamline assistance. We thank T. Werner for assistance with mass spectrometry experiments and data analysis, and the members of the Cellzome Biochemistry, Mass Spectrometry, and IT teams for outstanding expertise and diligence. This work was supported by a Wellcome-Beit Intermediate Clinical Fellowship to M. A. D. The Huntly lab is funded by the Medical Research Council (UK), Leukaemia Lymphoma Research (UK), the Wellcome Trust, The Leukemia & Lymphoma Society of America, Cancer Research UK (CRUK) and the NIHR Cambridge Biomedical Research Centre. This work in the Kouzarides laboratory was funded by a programme grant from Cancer Research UK (CRUK).