title: Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia.
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.
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.|Ludwig Boltzmann Institute for Cancer Research, Vienna 1090, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Grebien
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.|Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
authors.affiliation: Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, M5G 0A3, Canada.
authors.forename: Matthäus
authors.initials: M
authors.lastname: Getlik
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
authors.forename: Roberto
authors.initials: R
authors.lastname: Giambruno
authors.affiliation: MRC Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, Oxford OX3 9DS, United Kingdom.
authors.forename: Amit
authors.initials: A
authors.lastname: Grover
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam 3015 GE, The Netherlands.
authors.forename: Roberto
authors.initials: R
authors.lastname: Avellino
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
authors.forename: Anna
authors.initials: A
authors.lastname: Skucha
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
authors.forename: Sarah
authors.initials: S
authors.lastname: Vittori
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Kuznetsova
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Smil
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
authors.forename: Dalia
authors.initials: D
authors.lastname: Barsyte-Lovejoy
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
authors.forename: Fengling
authors.initials: F
authors.lastname: Li
authors.affiliation: Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, M5G 0A3, Canada.|Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, M5S 3M2, Canada.
authors.forename: Gennadiy
authors.initials: G
authors.lastname: Poda
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.|Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Schapira
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
authors.forename: Aiping
authors.initials: A
authors.lastname: Dong
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Senisterra
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
authors.forename: Alexey
authors.initials: A
authors.lastname: Stukalov
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
authors.forename: Kilian V M
authors.initials: KVM
authors.lastname: Huber
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schönegger
authors.affiliation: Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, M5G 0A3, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Marcellus
authors.affiliation: Department of Laboratory Medicine & Core Facility Genomics, Core Facilities, Medical University Vienna, Vienna 1090, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Bock
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brown
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna 1030, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
authors.forename: Keiryn L
authors.initials: KL
authors.lastname: Bennett
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada.|Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, M5G 0A3, Canada.
authors.forename: Rima
authors.initials: R
authors.lastname: Al-Awar
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam 3015 GE, The Netherlands.
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
authors.affiliation: MRC Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, Oxford OX3 9DS, United Kingdom.
authors.forename: Claus
authors.initials: C
authors.lastname: Nerlov
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.|Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 2M9, Canada.
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004095:Dihydropyridines / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D004095:Dihydropyridines; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C497422:KMT2A protein, human; C000601920:OICR-9429; D020033:Protein Isoforms; D054852:Small Molecule Libraries; C502547:WDR5 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase