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Nat Chem Biol. 2015 Aug;11(8):571-578. doi: 10.1038/nchembio.1859. Epub 2015 Jul 13.

Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia.

Author information

1
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
2
Ludwig Boltzmann Institute for Cancer Research, Vienna 1090, Austria.
3
Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
4
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
5
Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, M5G 0A3, Canada.
6
MRC Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, Oxford OX3 9DS, United Kingdom.
7
Department of Hematology, Erasmus University Medical Center, Rotterdam 3015 GE, The Netherlands.
8
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, M5S 3M2, Canada.
9
Department of Laboratory Medicine & Core Facility Genomics, Core Facilities, Medical University Vienna, Vienna 1090, Austria.
10
Research Institute of Molecular Pathology (IMP), Vienna 1030, Austria.
11
Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 2M9, Canada.
#
Contributed equally

Abstract

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.

PMID:
26167872
PMCID:
PMC4511833
DOI:
10.1038/nchembio.1859
[Indexed for MEDLINE]
Free PMC Article

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