Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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

DOI

10.1038/nchembio.1859

Type

Journal article

Journal

Nat Chem Biol

Publication Date

08/2015

Volume

11

Pages

571 - 578

Keywords

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