• An Erratum to this article was published on 17 September 2015

This article has been updated

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.

  • Compound C29H32F3N5O3

    OICR-9429

  • Compound C28H29F3N4O4

    OICR-0547

  • Compound C6H3BrFNO2

    4-bromo-1-fluoro-2-nitrobenzene

  • Compound C11H14BrN3O2

    1-(4-bromo-2-nitrophenyl)-4-methylpiperazine

  • Compound C17H26BNO3

    4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine

  • Compound C22H28N4O3

    4-((4'-(4-methylpiperazin-1-yl)-3'-nitro-[1,1'-biphenyl]-3-yl)methyl)morpholine

  • Compound C22H30N4O

    4-(4-methylpiperazin-1-yl)-3'-(morpholinomethyl)-[1,1'-biphenyl]-3-amine

  • Compound C7H4F3NO3

    6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylic acid

  • Compound C10H11BrN2O3

    4-(4-bromo-2-nitrophenyl)morpholine

  • Compound C21H25N3O4

    4-((4'-morpholino-3'-nitro-[1,1'-biphenyl]-3-yl)methyl)morpholine

  • Compound C21H27N3O2

    4-morpholino-3'-(morpholinomethyl)-[1,1'-biphenyl]-3-amine

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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.

Author information

Author notes

    • Florian Grebien
    • , Masoud Vedadi
    • , Matthäus Getlik
    • , Cheryl H Arrowsmith
    •  & Giulio Superti-Furga

    These authors contributed equally to this work.

Affiliations

  1. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

    • Florian Grebien
    • , Roberto Giambruno
    • , Anna Skucha
    • , Sarah Vittori
    • , Alexey Stukalov
    • , Kilian V M Huber
    • , Andreas Schönegger
    • , Christoph Bock
    • , Keiryn L Bennett
    •  & Giulio Superti-Furga
  2. Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.

    • Florian Grebien
  3. Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.

    • Masoud Vedadi
    • , Ekaterina Kuznetsova
    • , David Smil
    • , Dalia Barsyte-Lovejoy
    • , Fengling Li
    • , Matthieu Schapira
    • , Hong Wu
    • , Aiping Dong
    • , Guillermo Senisterra
    • , Peter J Brown
    •  & Cheryl H Arrowsmith
  4. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.

    • Masoud Vedadi
    • , Matthieu Schapira
    •  & Rima Al-awar
  5. Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

    • Matthäus Getlik
    • , Gennadiy Poda
    • , Richard Marcellus
    •  & Rima Al-awar
  6. MRC Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK.

    • Amit Grover
    •  & Claus Nerlov
  7. Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands.

    • Roberto Avellino
    •  & Ruud Delwel
  8. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.

    • Gennadiy Poda
  9. Department of Laboratory Medicine and Core Facility Genomics, Core Facilities, Medical University Vienna, Vienna, Austria.

    • Martin Bilban
  10. Research Institute of Molecular Pathology, Vienna, Austria.

    • Johannes Zuber
  11. Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

    • Cheryl H Arrowsmith
  12. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

    • Cheryl H Arrowsmith
  13. Center for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria.

    • Giulio Superti-Furga

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

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

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    Supplementary Results, Supplementary Tables 1–7, Supplementary Figures 1–16 and Supplementary Note.

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https://doi.org/10.1038/nchembio.1859

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