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 DoehnerRuud Delwel, AK Burnett, P Jeffrey, G Drewes, K Lee, BJP Huntly, T Kouzarides

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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 therapies(1). 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(2,3). Here we use a global proteomic strategy to demonstrate that MLL fusions, as part of SEC(2,3) 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.
Original languageUndefined/Unknown
Pages (from-to)529-533
Number of pages5
JournalNature
Volume478
Issue number7370
DOIs
Publication statusPublished - 2011

Research programs

  • EMC MM-02-41-03

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