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| Home > Publications database > Oncogene EVI1 drives acute myeloid leukemia via a targetable interaction with CTBP2. |
| Home > Publications database > Oncogene EVI1 drives acute myeloid leukemia via a targetable interaction with CTBP2. |
| Journal Article | DKFZ-2024-01051 |
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2024
Assoc.
Washington, DC [u.a.]
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Please use a persistent id in citations: doi:10.1126/sciadv.adk9076
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.
Keyword(s): Leukemia, Myeloid, Acute: genetics (MeSH) ; Leukemia, Myeloid, Acute: metabolism (MeSH) ; Leukemia, Myeloid, Acute: pathology (MeSH) ; MDS1 and EVI1 Complex Locus Protein: metabolism (MeSH) ; MDS1 and EVI1 Complex Locus Protein: genetics (MeSH) ; Alcohol Oxidoreductases: metabolism (MeSH) ; Alcohol Oxidoreductases: genetics (MeSH) ; Humans (MeSH) ; Animals (MeSH) ; DNA-Binding Proteins: metabolism (MeSH) ; DNA-Binding Proteins: genetics (MeSH) ; Mice (MeSH) ; Co-Repressor Proteins: metabolism (MeSH) ; Co-Repressor Proteins: genetics (MeSH) ; Protein Binding (MeSH) ; Cell Line, Tumor (MeSH) ; Cell Proliferation (MeSH) ; Cell Transformation, Neoplastic: genetics (MeSH) ; Cell Transformation, Neoplastic: metabolism (MeSH) ; Transcription Factors: metabolism (MeSH) ; Transcription Factors: genetics (MeSH)
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