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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.

Original publication




Journal article


Nat Chem Biol

Publication Date





571 - 578


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