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Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia
Open accessAbstract
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.
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“Potent and selective compounds are also targeting the central cavity of WDR5, another WDR DCAF E3 ligase 71 .”
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Metadata
- Authors
- Grebien, F., Vedadi, M., Getlik, M., Giambruno, R., Grover, A., Avellino, R., Skucha, A., Vittori, S., Kuznetsova, E., Smil, D., Barsyte-Lovejoy, D., Li, F., Poda, G., Schapira, M., Wu, H., Dong, A., Senisterra, G., Stukalov, A., Huber, K. V. M., Schönegger, A., Marcellus, R., Bilban, M., Bock, C., Brown, P. J., Zuber, J., Bennett, K. L., Al-awar, R., Delwel, R., Nerlov, C., Arrowsmith, C. H., & Superti-Furga, G.
- Affiliations
- Austrian Academy of Sciences (AT)
- University of Toronto (CA)
- Ontario Institute for Cancer Research (CA)
- MRC Weatherall Institute of Molecular Medicine (GB)
- Erasmus MC (NL)
- Medical University of Vienna (AT)
- Research Institute of Molecular Pathology (AT)
- Corresponding author
- Grebien, Florian
- Arrowsmith, Cheryl H
- ORCID
- Grebien, Florian
- Vedadi, Masoud
- Giambruno, Roberto
- Grover, Amit
- Avellino, Roberto
- Skucha, Anna
- Kuznetsova, Ekaterina
- Smil, David
- Li, Fengling
- Schapira, Matthieu
- Dong, Aiping
- Stukalov, Alexey
- Huber, Kilian V M
- Marcellus, Richard
- Bilban, Martin
- Bock, Christoph
- Brown, Peter J
- Zuber, Johannes
- Bennett, Keiryn L
- Delwel, Ruud
- Nerlov, Claus
- Arrowsmith, Cheryl H
- Superti-Furga, Giulio
- Venue
- Nature Chemical Biology
- Published
- 2015-07-13
- Volume
- 11
- Issue
- 8
- Pages
- 571-578
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W4294309410
- Cited by
- 284
- References
- 59
- Citations by year
- 2026: 19 · 2025: 20 · 2024: 33 · 2023: 26 · 2022: 27 · 2021: 35 · 2020: 21 · 2019: 30 · 2018: 25 · 2017: 16 · 2016: 24 · 2015: 8
- FWCI
- 20.44
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-09-17)
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- Nature Chemical Biology (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (106169, 092809/Z/10/Z)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- WDR5, acute myeloid leukemia, CEBPA mutation, H3K4me3, myeloid differentiation, small molecule drug targets
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