Oncogene EVI1 Drives Acute Myeloid Leukemia Via a Targetable Interaction with CTBP2
- 1. Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands; Oncode Institute, Utrecht
- 2. Stem Cell Group, UCL Cancer Institute, University College London, London, United Kingdom
- 3. Department of Hematology, Amsterdam UMC location VUMc, Amsterdam, The Netherlands
- 4. Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany; Division of Experimental Hematology, German Cancer Research Center, DKFZ, 69120 Heidelberg, Germany
- 5. Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
- 6. Proteomics Center, Erasmus MC, Rotterdam, Netherlands
Description
Acute myeloid leukemia (AML) driven by the activation of EVI1 due to chromosome 3q26/MECOM rearrangements is incurable. Since transcription factors like 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 interaction with CTBP1 and CTBP2 via a single PLDLS motif in EVI1 is indispensable for leukemic transformation. A 4x 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. Our findings may also have important implications for other tumour types with aberrant expression of EVI1 or for cancers transformed by other CTBP1/2 dependent oncogenic transcription factors.
Files
AlphaFold_Chimerax_Contacts.txt
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