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 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.