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

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.

Pubmed ID: 21964340


  • Dawson MA
  • Prinjha RK
  • Dittmann A
  • Giotopoulos G
  • Bantscheff M
  • Chan WI
  • Robson SC
  • Chung CW
  • Hopf C
  • Savitski MM
  • Huthmacher C
  • Gudgin E
  • Lugo D
  • Beinke S
  • Chapman TD
  • Roberts EJ
  • Soden PE
  • Auger KR
  • Mirguet O
  • Doehner K
  • Delwel R
  • Burnett AK
  • Jeffrey P
  • Drewes G
  • Lee K
  • Huntly BJ
  • Kouzarides T



Publication Data

October 27, 2011

Associated Grants

  • Agency: Wellcome Trust, Id: 092096
  • Agency: Medical Research Council, Id: G0800784
  • Agency: Medical Research Council, Id: G116/187
  • Agency: Cancer Research UK, Id:
  • Agency: Medical Research Council, Id:
  • Agency: Wellcome Trust, Id:

Mesh Terms

  • Animals
  • Cell Line, Tumor
  • Chromatin
  • Chromatin Immunoprecipitation
  • Disease Models, Animal
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Heterocyclic Compounds with 4 or More Rings
  • Humans
  • Leukemia, Myeloid, Acute
  • Mice
  • Models, Molecular
  • Multiprotein Complexes
  • Myeloid-Lymphoid Leukemia Protein
  • Oncogene Proteins, Fusion
  • Protein Binding
  • Proteomics
  • Transcription Factors
  • Transcription, Genetic