title: Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia.
abstract: 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.
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research and Addenbrookes Hospital, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Dawson
authors.forename: Rab K
authors.initials: RK
authors.lastname: Prinjha
authors.forename: Antje
authors.initials: A
authors.lastname: Dittmann
authors.forename: George
authors.initials: G
authors.lastname: Giotopoulos
authors.forename: Marcus
authors.initials: M
authors.lastname: Bantscheff
authors.forename: Wai-In
authors.initials: WI
authors.lastname: Chan
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Robson
authors.forename: Chun-wa
authors.initials: CW
authors.lastname: Chung
authors.forename: Carsten
authors.initials: C
authors.lastname: Hopf
authors.forename: Mikhail M
authors.initials: MM
authors.lastname: Savitski
authors.forename: Carola
authors.initials: C
authors.lastname: Huthmacher
authors.forename: Emma
authors.initials: E
authors.lastname: Gudgin
authors.forename: Dave
authors.initials: D
authors.lastname: Lugo
authors.forename: Soren
authors.initials: S
authors.lastname: Beinke
authors.forename: Trevor D
authors.initials: TD
authors.lastname: Chapman
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Roberts
authors.forename: Peter E
authors.initials: PE
authors.lastname: Soden
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Auger
authors.forename: Olivier
authors.initials: O
authors.lastname: Mirguet
authors.forename: Konstanze
authors.initials: K
authors.lastname: Doehner
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
authors.forename: Alan K
authors.initials: AK
authors.lastname: Burnett
authors.forename: Phillip
authors.initials: P
authors.lastname: Jeffrey
authors.forename: Gerard
authors.initials: G
authors.lastname: Drewes
authors.forename: Kevin
authors.initials: K
authors.lastname: Lee
authors.forename: Brian J P
authors.initials: BJ
authors.lastname: Huntly
authors.forename: Tony
authors.initials: T
authors.lastname: Kouzarides
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D040901:Proteomics; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D002843:Chromatin; C568713:GSK1210151A; D006576:Heterocyclic Compounds, 4 or More Rings; D046912:Multiprotein Complexes; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein