Oncogene EVI1 drives acute myeloid leukemia via a targetable interaction with CTBP2
Open accessPublished version of a preprint
Abstract
Acute myeloid leukemia (AML) driven by the activation of EVI1 due to chromosome 3q26/ MECOM rearrangements is incurable. Because transcription factors such as EVI1 are notoriously hard to target, insight into the mechanism by which EVI1 drives myeloid transformation could provide alternative avenues for therapy. Applying protein folding predictions combined with proteomics technologies, we demonstrate that interaction of EVI1 with CTBP1 and CTBP2 via a single PLDLS motif is indispensable for leukemic transformation. A 4× PLDLS repeat construct outcompetes binding of EVI1 to CTBP1 and CTBP2 and inhibits proliferation of 3q26/ MECOM rearranged AML in vitro and in xenotransplant models. This proof-of-concept study opens the possibility to target one of the most incurable forms of AML with specific EVI1-CTBP inhibitors. This has important implications for other tumor types with aberrant expression of EVI1 and for cancers transformed by different CTBP-dependent oncogenic transcription factors.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
A Single Oncogenic Enhancer Rearrangement Causes Concomitant EVI1 and GATA2 Deregulation in Leukemia
Gröschel, S., Sanders, M. A., Hoogenboezem, R., de Wit, E., Bouwman, B. A. M., Erpelinck, C., van der Velden, V. H. J., Havermans, M., Avellino, R., van Lom, K., et al. (2014) · Cell · doi:10.1016/j.cell.2014.02.019 · Cited by 687 · see citing works
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- Authors
- Pastoors, D., Havermans, M., Mulet-Lazaro, R., Brian, D., Noort, W., Grasel, J., Hoogenboezem, R., Smeenk, L., Demmers, J. A. A., Milsom, M. D., Enver, T., Groen, R. W. J., Bindels, E., & Delwel, R.
- Affiliations
- Oncode Institute (NL)
- Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
- University College London (GB)
- Cancer Center Amsterdam (NL)
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany.
- Erasmus MC Cancer Institute (NL)
- Erasmus MC (NL)
- German Cancer Research Center (DE)
- Corresponding author
- Delwel, Ruud
- ORCID
- Venue
- Science Advances
- Published
- 2024-05-17
- Volume
- 10
- Issue
- 20
- Pages
- eadk9076-eadk9076
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC11095456
- OpenAlex
- W4396943625
- Cited by
- 15
- References
- 2
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 3
- FWCI
- 4.65
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Science Advances (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (acceptedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, cc-by)
- Funders
- Radboud Universiteit
- 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
- EVI1, acute myeloid leukemia, CtBP2, CtBP1, oncogenes, protein-protein interaction, leukemic transformation, small molecule inhibitors, transcription factors
- MeSH terms
- MDS1 and EVI1 Complex Locus Protein, Alcohol Oxidoreductases, Animals, Cell Transformation, Neoplastic, DNA-Binding Proteins, Humans, Protein Binding, Transcription Factors, Leukemia, Myeloid, Acute, Cell Line, Tumor, Cell Proliferation, Mice, Co-Repressor Proteins
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