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

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16994
    99.93%, OICR-9429 Negative Control