e-Article
Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia.
Document Type
Article
Author
Grebien, Florian; Vedadi, Masoud; Getlik, Matthäus; Giambruno, Roberto; Grover, Amit; Avellino, Roberto; Skucha, Anna; Vittori, Sarah; Kuznetsova, Ekaterina; Smil, David; Barsyte-Lovejoy, Dalia; Li, Fengling; Poda, Gennadiy; Schapira, Matthieu; Wu, Hong; Dong, Aiping; Senisterra, Guillermo; Stukalov, Alexey; Huber, Kilian V M; Schönegger, Andreas
Source
Subject
*SMALL molecules
*ACUTE myeloid leukemia
*HISTONE methyltransferases
*CARRIER proteins
*PROTEIN-protein interactions
*PROTEIN expression
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Language
ISSN
1552-4450
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. [ABSTRACT FROM AUTHOR]