Journal
NATURE CHEMICAL BIOLOGY
Volume 11, Issue 8, Pages 571-578Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.1859
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Funding
- Austrian Science Fund (FWF) [P22282-B11]
- FP7-PEOPLE-ITN Project HemID [289611]
- Austrian Academy of Sciences
- European Research Council (ERC) [ERC-2009-AdG-250179-i-FIVE]
- AbbVie [1097737]
- Bayer
- Boehringer Ingelheim
- Genome Canada through the Ontario Genomics Institute [OGI-055]
- GlaxoSmithKline
- Janssen
- Lilly Canada
- Novartis Research Foundation
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Takeda
- Wellcome Trust [092809/Z/10/Z]
- Government of Ontario
- Leukemia and Lymphoma Society of Canada
- MRC [G0701761, G0900892, MC_UU_12009/7] Funding Source: UKRI
- Austrian Science Fund (FWF) [P 22282] Funding Source: researchfish
- Medical Research Council [G0701761, MC_UU_12009/7, G0900892] Funding Source: researchfish
- Worldwide Cancer Research [11-0724] Funding Source: researchfish
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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-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.
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