Acute myeloid leukemia (AML) driven by the activation of the EVI1 gene is incurable and transcription factors such as EVI1 are notoriously hard to target. In a new study, Oncode Investigator Ruud Delwel and his team at Erasmus MC offer insight into the mechanism by which this gene drives myeloid transformation. The study is now published in Science Advances. These findings can provide novel ways for therapy.
The EVI1 gene needs a partner gene/protein, which is called CTBP, to fully transform hematopoietic progenitor cells. Delwel’s study shows this and reveals that an unique 5 amino acid PLDLS motif in EVI1 is essential for this interaction. Applying protein folding predictions combined with proteomics technologies, the researchers demonstrated that the interaction of EVI1 with CTBP1 and CTBP2 via a single PLDLS motif is indispensable for leukemic transformation.
This interaction with CTBP was predicted by AI (AlphaFold) and validated biochemically. Further on, the researchers showed that when this interaction was blocked in a biological model, leukemic transformation was reverted in vitro and in vivo (In a xenotransplant model). A 4x PLDLS repeat construct outcompeted binding of EVI1 to CTBP1 and CTBP2 and inhibited 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.
In collaboration with Oncode Investigator Sebastian Pomplun, Delwel’s team is now trying to find ways to chemically block EVI1 to CTBP interaction in patients cells.
Read this interview with Ruud Delwel and his team published in Amazing Erasmus MC (in Dutch).
Read the full manuscript here.