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

  • Nat Chem Biol. 2015 Aug;11(8):571-578. doi: 10.1038/nchembio.1859.
Florian Grebien   #  1  2 ,  Masoud Vedadi   #  3  4 ,  Matthäus Getlik   #  5 ,  Roberto Giambruno  1 ,  Amit Grover  6 ,  Roberto Avellino  7 ,  Anna Skucha  1 ,  Sarah Vittori  1 ,  Ekaterina Kuznetsova  3 ,  David Smil  3 ,  Dalia Barsyte-Lovejoy  3 ,  Fengling Li  3 ,  Gennadiy Poda  5  8 ,  Matthieu Schapira  3  4 ,  Hong Wu  3 ,  Aiping Dong  3 ,  Guillermo Senisterra  3 ,  Alexey Stukalov  1 ,  Kilian V M Huber  1 ,  Andreas Schönegger  1 ,  Richard Marcellus  5 ,  Martin Bilban  9 ,  Christoph Bock  1 ,  Peter J Brown  3 ,  Johannes Zuber  10 ,  Keiryn L Bennett  1 ,  Rima Al-Awar  4  5 ,  Ruud Delwel  7 ,  Claus Nerlov  6 ,  Cheryl H Arrowsmith   #  3  11 ,  Giulio Superti-Furga   #  1
Affiliations
  • 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.
PMID: 26167872 DOI: 10.1038/nchembio.1859
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.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16994
    OICR-0547
    99.85%, OICR-9429 Negative Control
    target: WDR5
    Research Areas: Cancer