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

Abstract

Rearrangements of the MLL (mixed lineage leukaemia) gene, and chimaeric MLL-fusion proteins, occur in a number of aggressive leukaemias including acute myeloid leukemia (AML). Tony Kouzarides and colleagues now find that MLL-fusion proteins are associated with BET family proteins in transcription factor complexes. GSK1210151A (I-BET151), a new small-molecule inhibitor of the interaction between BET family proteins and specific chromatin marks, is shown to have efficacy against AML cells in vitro and in mouse models, suggesting a new therapeutic strategy for AML. 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.