Functional interdependence of BRD4 and DOT1L in MLL leukemia

O Gilan; EYN Lam; I Becher; D Lugo; E Cannizzaro; G Joberty; A Ward; M Wiese; CY Fong; S Ftouni; D Tyler; K Stanley; L MacPherson; CF Weng; YC Chan; M Ghisi; D Smil; C Carpenter; P Brown; N Garton; ME Blewitt; AJ Bannister; T Kouzarides; BJP Huntly; RW Johnstone; G Drewes; SJ Dawson; CH Arrowsmith; P Grandi; RK Prinjha; MA Dawson

Journal article

Functional interdependence of BRD4 and DOT1L in MLL leukemia

O Gilan, EYN Lam, I Becher, D Lugo, E Cannizzaro, G Joberty, A Ward, M Wiese, CY Fong, S Ftouni, D Tyler, K Stanley, L MacPherson, CF Weng, YC Chan, M Ghisi, D Smil, C Carpenter, P Brown, N Garton Show all

Nature Structural and Molecular Biology | NATURE PUBLISHING GROUP | Published : 2016

DOI: 10.1038/nsmb.3249

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 betw..

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University of Melbourne Researchers

Enid Lam Author

Laura MacPherson Author

Marnie Blewitt Author

Ricky Johnstone Author

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Grants

Awarded by Medical Research Council

Funding Acknowledgements

A postdoctoral Fellowship awarded to O.G. from Leukaemia Foundation Australia partly supported this work. A mid-career Fellowship awarded to E.Y.N.L. from the Victoria Cancer Agency partly supported this work. A Senior Leukaemia Foundation Australia Fellowship and VESKI Innovation Fellowship currently support M.A.D. The National Health and Medical Research Council of Australia (1066545 (M.A.D.), 1085015 (M.A.D.), 1106444 (M.A.D.)) and Leukaemia Foundation Australia fund M.A.D.'s laboratory. This work was also funded in part by the Structural Genomics Consortium, a registered charity (no. 1097737) that received funds from AbbVie; Bayer; Boehringer Ingelheim; Genome Canada through the Ontario Genomics Institute (OGI-055); GlaxoSmithKline; Janssen; Lilly Canada; the Novartis Research Foundation; the Ontario Ministry of Economic Development and Innovation; Pfizer; Takeda; and the Wellcome Trust (092809/Z/10/Z).