Pharmacological targeting of the Wdr5-MLL interaction in C/EBP alpha N-terminal leukemia

F Grebien, M Vedadi, M Getlik, R Giambruno, A Grover, Roberto Avellino, A Skucha, S Vittori, E Kuznetsova, D Smil, D Barsyte-Lovejoy, FL Li, G Poda, M Schapira, H Wu, AP Dong, G Senisterra, A Stukalov, KVM Huber, A SchoneggerR Marcellus, M Bilban, C Bock, PJ Brown, J Zuber, KL Bennett, R Al-Awar, Ruud Delwel, C Nerlov, CH Arrowsmith, G Superti-Furga

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171 Citations (Scopus)

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-alpha (C/EBP alpha) 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/EBP alpha 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 languageUndefined/Unknown
Pages (from-to)571-U122
JournalNature Chemical Biology
Volume11
Issue number8
DOIs
Publication statusPublished - 2015

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