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000290235 1001_ $$00000-0002-5322-1961$$aPastoors, Dorien$$b0
000290235 245__ $$aOncogene EVI1 drives acute myeloid leukemia via a targetable interaction with CTBP2.
000290235 260__ $$aWashington, DC [u.a.]$$bAssoc.$$c2024
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000290235 520__ $$aAcute 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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000290235 650_2 $$2MeSH$$aLeukemia, Myeloid, Acute: genetics
000290235 650_2 $$2MeSH$$aLeukemia, Myeloid, Acute: metabolism
000290235 650_2 $$2MeSH$$aLeukemia, Myeloid, Acute: pathology
000290235 650_2 $$2MeSH$$aMDS1 and EVI1 Complex Locus Protein: metabolism
000290235 650_2 $$2MeSH$$aMDS1 and EVI1 Complex Locus Protein: genetics
000290235 650_2 $$2MeSH$$aAlcohol Oxidoreductases: metabolism
000290235 650_2 $$2MeSH$$aAlcohol Oxidoreductases: genetics
000290235 650_2 $$2MeSH$$aHumans
000290235 650_2 $$2MeSH$$aAnimals
000290235 650_2 $$2MeSH$$aDNA-Binding Proteins: metabolism
000290235 650_2 $$2MeSH$$aDNA-Binding Proteins: genetics
000290235 650_2 $$2MeSH$$aMice
000290235 650_2 $$2MeSH$$aCo-Repressor Proteins: metabolism
000290235 650_2 $$2MeSH$$aCo-Repressor Proteins: genetics
000290235 650_2 $$2MeSH$$aProtein Binding
000290235 650_2 $$2MeSH$$aCell Line, Tumor
000290235 650_2 $$2MeSH$$aCell Proliferation
000290235 650_2 $$2MeSH$$aCell Transformation, Neoplastic: genetics
000290235 650_2 $$2MeSH$$aCell Transformation, Neoplastic: metabolism
000290235 650_2 $$2MeSH$$aTranscription Factors: metabolism
000290235 650_2 $$2MeSH$$aTranscription Factors: genetics
000290235 7001_ $$00009-0009-7996-9458$$aHavermans, Marije$$b1
000290235 7001_ $$00000-0003-0298-7948$$aMulet-Lazaro, Roger$$b2
000290235 7001_ $$00000-0002-3980-7341$$aBrian, Duncan$$b3
000290235 7001_ $$00009-0007-0943-8729$$aNoort, Willy$$b4
000290235 7001_ $$0P:(DE-He78)f3428d5eb2ce372b596cca4354cbfaa8$$aGräsel, Julius$$b5
000290235 7001_ $$aHoogenboezem, Remco$$b6
000290235 7001_ $$00000-0001-7025-8515$$aSmeenk, Leonie$$b7
000290235 7001_ $$00000-0002-8757-9611$$aDemmers, Jeroen A A$$b8
000290235 7001_ $$0P:(DE-He78)7b613cadb8c16ce178713e15b85d982c$$aMilsom, Michael$$b9$$udkfz
000290235 7001_ $$aEnver, Tariq$$b10
000290235 7001_ $$00000-0002-5010-4604$$aGroen, Richard W J$$b11
000290235 7001_ $$00000-0001-9502-669X$$aBindels, Eric$$b12
000290235 7001_ $$aDelwel, Ruud$$b13
000290235 773__ $$0PERI:(DE-600)2810933-8$$a10.1126/sciadv.adk9076$$gVol. 10, no. 20, p. eadk9076$$n20$$peadk9076$$tScience advances$$v10$$x2375-2548$$y2024
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