TY  - JOUR
AU  - Pastoors, Dorien
AU  - Havermans, Marije
AU  - Mulet-Lazaro, Roger
AU  - Brian, Duncan
AU  - Noort, Willy
AU  - Gräsel, Julius
AU  - Hoogenboezem, Remco
AU  - Smeenk, Leonie
AU  - Demmers, Jeroen A A
AU  - Milsom, Michael
AU  - Enver, Tariq
AU  - Groen, Richard W J
AU  - Bindels, Eric
AU  - Delwel, Ruud
TI  - Oncogene EVI1 drives acute myeloid leukemia via a targetable interaction with CTBP2.
JO  - Science advances
VL  - 10
IS  - 20
SN  - 2375-2548
CY  - Washington, DC [u.a.]
PB  - Assoc.
M1  - DKFZ-2024-01051
SP  - eadk9076
PY  - 2024
AB  - 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.
KW  - Leukemia, Myeloid, Acute: genetics
KW  - Leukemia, Myeloid, Acute: metabolism
KW  - Leukemia, Myeloid, Acute: pathology
KW  - MDS1 and EVI1 Complex Locus Protein: metabolism
KW  - MDS1 and EVI1 Complex Locus Protein: genetics
KW  - Alcohol Oxidoreductases: metabolism
KW  - Alcohol Oxidoreductases: genetics
KW  - Humans
KW  - Animals
KW  - DNA-Binding Proteins: metabolism
KW  - DNA-Binding Proteins: genetics
KW  - Mice
KW  - Co-Repressor Proteins: metabolism
KW  - Co-Repressor Proteins: genetics
KW  - Protein Binding
KW  - Cell Line, Tumor
KW  - Cell Proliferation
KW  - Cell Transformation, Neoplastic: genetics
KW  - Cell Transformation, Neoplastic: metabolism
KW  - Transcription Factors: metabolism
KW  - Transcription Factors: genetics
LB  - PUB:(DE-HGF)16
C6  - pmid:38748792
DO  - DOI:10.1126/sciadv.adk9076
UR  - https://inrepo02.dkfz.de/record/290235
ER  -