Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia

Dawson, Mark A., Prinjha, Rab K., Dittmann, Antje, Giotopoulos, George, Bantscheff, Marcus, Chan, Wai-In, Robson, Samuel C., Chung, Chun-wa, Hopf, Carsten, Savitski, Mikhail M., Huthmacher, Carola, Gudgin, Emma, Lugo, Dave, Beinke, Soren, Chapman, Trevor D., Roberts, Emma J., Soden, Peter E., Auger, Kurt R., Mirguet, Olivier, Doehner, Konstanze, Delwel, Ruud, Burnett, Alan Kenneth, Jeffrey, Phillip, Drewes, Gerard, Lee, Kevin, Huntly, Brian J. P. and Kouzarides, Tony 2011. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478 (7370) , pp. 529-533. 10.1038/nature10509

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Abstract

Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which are often refractory to conventional therapies1. 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 induction2, 3. Here we use a global proteomic strategy to demonstrate that MLL fusions, as part of SEC2, 3 and the polymerase-associated factor complex (PAFc)4, 5, are associated with the BET family of acetyl-lysine recognizing, chromatin ‘adaptor’ proteins. These data provided the basis for therapeutic intervention in MLL-fusion leukaemia, via the displacement of the BET family of proteins from chromatin. We show that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in two human leukaemia cell lines with different MLL fusions alters the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes (BCL2, C-MYC and CDK6) through the displacement of BRD3/4, PAFc and SEC components from chromatin. In vivo studies indicate that I-BET151 has significant therapeutic value, providing survival benefit in two distinct mouse models of murine MLL–AF9 and human MLL–AF4 leukaemia. Finally, the efficacy of I-BET151 against human leukaemia stem cells is demonstrated, providing further evidence of its potent therapeutic potential. These findings establish the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords:	Cancer; Cell biology; Molecular biology; Therapeutics
Publisher:	Nature Publishing Group
ISSN:	0028-0836
Last Modified:	25 Jun 2017 03:29
URI:	https://orca.cardiff.ac.uk/id/eprint/29828

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