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

An Erratum to this article was published on 17 September 2015

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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.

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Figure 1: C/EBPα p30 preferably interacts with Wdr5 and the SET/MLL HMT complex, leading to increased colocalization of p30 and H3K4me3 on chromatin.
Figure 2: Loss of Wdr5 restores granulocytic differentiation potential in C/EBPα p30-expressing cells.
Figure 3: Wdr5 is required to maintain C/EBPα p30-dependent self-renewal in vitro and in vivo.
Figure 4: OICR-9429 binds WDR5 in the MLL WIN motif-binding pocket.
Figure 5: OICR-9429 is a small-molecule antagonist of the Wdr5-MLL interaction.
Figure 6: Pharmacological antagonism of the WDR5-MLL interaction by OICR-9429 selectively affects p30-expressing cells.

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  • 20 August 2015

    In the author list, affiliation and correspondence information for Cheryl Arrowsmith was missing. Her name should be accompanied by affiliation number 3 (signifying the Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada) and by an asterisk indicating her status as a corresponding author. These errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank M. Gridling, M. Planyavsky, D. Printz and A. Spittler for experimental help and K. Kandasamy and M. Schuster for bioinformatic help. Next-generation sequencing was performed at the Campus Science Support Facilities Next-Generation Sequencing Unit (http://www.csf.ac.at/). F.G. and R.G. were funded by the Austrian Science Fund (FWF grant P22282-B11). A. Skucha is supported by FP7-PEOPLE-2011-ITN Project HemID (289611). The Superti-Furga laboratory is supported by the Austrian Academy of Sciences and by European Research Council (ERC) grant ERC-2009-AdG-250179-i-FIVE. The Structural Genomics Consortium is a registered charity (no. 1097737) that receives funds from AbbVie, Bayer, Boehringer Ingelheim, Genome Canada through the Ontario Genomics Institute (OGI-055), GlaxoSmithKline, Janssen, Lilly Canada, the Novartis Research Foundation, the Ontario Ministry of Economic Development and Innovation, Pfizer, Takeda and the Wellcome Trust (092809/Z/10/Z). The Ontario Institute for Cancer Research is funded by the Government of Ontario. Funding was also provided by the Leukemia and Lymphoma Society of Canada.

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F.G., M.V., R.G., A.G., R.A., A. Skucha, S.V., E.K., D.B.-L., F.L, G.S., K.V.M.H. and R.M. planned, performed and analyzed biochemical, biophysical, cellular and in vivo experiments. M.G., D.S., G.P., M.S., P.J.B. and R.A. contributed to chemical design and synthesis of OICR-9429 and OICR-0547. H.W., A.D. and M.S. solved and analyzed the X-ray crystal structure of WDR5 in complex with OICR-9429. A. Stukalov, A. Schönegger, M.B. and C.B. performed bioinformatic analyses. J.Z., K.L.B., R.D. and C.N. provided access to vital tools and technologies, planned experiments and analyzed results. F.G., M.V., P.J.B., R.A., C.H.A. and G.S.-F. designed the study, planned experiments, analyzed results and wrote the paper.

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Correspondence to Florian Grebien, Cheryl H Arrowsmith or Giulio Superti-Furga.

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Grebien, F., Vedadi, M., Getlik, M. et al. Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia. Nat Chem Biol 11, 571–578 (2015). https://doi.org/10.1038/nchembio.1859

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