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. Epub 2015 Jul 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Biphenyl Compounds / pharmacology*
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Dihydropyridines / pharmacology*
  • Gene Expression Regulation, Neoplastic*
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Molecular Docking Simulation
  • Molecular Sequence Data
  • Molecular Targeted Therapy
  • Mutation
  • Myeloid-Lymphoid Leukemia Protein / antagonists & inhibitors*
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Myeloid-Lymphoid Leukemia Protein / metabolism
  • Protein Binding
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Structure, Tertiary
  • Signal Transduction
  • Small Molecule Libraries / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Biphenyl Compounds
  • CCAAT-Enhancer-Binding Proteins
  • CEBPA protein, human
  • Dihydropyridines
  • Histones
  • KMT2A protein, human
  • OICR-9429
  • Protein Isoforms
  • Small Molecule Libraries
  • WDR5 protein, human
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase

Associated data

  • GDB/4QL1
  • PubChem-Substance/251973332
  • PubChem-Substance/251973333
  • PubChem-Substance/251973334
  • PubChem-Substance/251973335
  • PubChem-Substance/251973336
  • PubChem-Substance/251973337
  • PubChem-Substance/251973338
  • PubChem-Substance/251973339
  • PubChem-Substance/251973340
  • PubChem-Substance/251973341
  • PubChem-Substance/251973342