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PDBsum entry 4ql1
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Transcription/inhibitor
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PDB id
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4ql1
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References listed in PDB file
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Key reference
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Title
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Pharmacological targeting of the wdr5-Mll interaction in c/ebpα n-Terminal leukemia.
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Authors
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F.Grebien,
M.Vedadi,
M.Getlik,
R.Giambruno,
A.Grover,
R.Avellino,
A.Skucha,
S.Vittori,
E.Kuznetsova,
D.Smil,
D.Barsyte-Lovejoy,
F.Li,
G.Poda,
M.Schapira,
H.Wu,
A.Dong,
G.Senisterra,
A.Stukalov,
K.V.Huber,
A.Schönegger,
R.Marcellus,
M.Bilban,
C.Bock,
P.J.Brown,
J.Zuber,
K.L.Bennett,
R.Al-Awar,
R.Delwel,
C.Nerlov,
C.H.Arrowsmith,
G.Superti-Furga.
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Ref.
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Nat Chem Biol, 2015,
11,
571-578.
[DOI no: ]
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PubMed id
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Abstract
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The CEBPA gene is mutated in 9% of patients with acute myeloid leukemia (AML).
Selective expression of a short (30-kDa) CCAAT-enhancer binding protein-α
(C/EBPα) translational isoform, termed p30, represents the most common type of
CEBPA mutation in AML. The molecular mechanisms underlying p30-mediated
transformation remain incompletely understood. We show that C/EBPα p30, but not
the normal p42 isoform, preferentially interacts with Wdr5, a key component of
SET/MLL (SET-domain/mixed-lineage leukemia) histone-methyltransferase complexes.
Accordingly, p30-bound genomic regions were enriched for MLL-dependent H3K4me3
marks. The p30-dependent increase in self-renewal and inhibition of myeloid
differentiation required Wdr5, as downregulation of the latter inhibited
proliferation and restored differentiation in p30-dependent AML models.
OICR-9429 is a new small-molecule antagonist of the Wdr5-MLL interaction. This
compound selectively inhibited proliferation and induced differentiation in
p30-expressing human AML cells. Our data reveal the mechanism of p30-dependent
transformation and establish the essential p30 cofactor Wdr5 as a therapeutic
target in CEBPA-mutant AML.
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