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PDBsum entry 3zyu
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Signaling protein
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PDB id
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3zyu
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References listed in PDB file
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Key reference
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Title
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Inhibition of bet recruitment to chromatin as an effective treatment for mll-Fusion leukaemia.
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Authors
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M.A.Dawson,
R.K.Prinjha,
A.Dittmann,
G.Giotopoulos,
M.Bantscheff,
W.I.Chan,
S.C.Robson,
C.W.Chung,
C.Hopf,
M.M.Savitski,
C.Huthmacher,
E.Gudgin,
D.Lugo,
S.Beinke,
T.D.Chapman,
E.J.Roberts,
P.E.Soden,
K.R.Auger,
O.Mirguet,
K.Doehner,
R.Delwel,
A.K.Burnett,
P.Jeffrey,
G.Drewes,
K.Lee,
B.J.Huntly,
T.Kouzarides.
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Ref.
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Nature, 2011,
478,
529-533.
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PubMed id
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Abstract
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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.
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