Dataset Information

Oncogene EVI1 Drives Acute Myeloid Leukemia Via a Targetable Interaction with CTBP2

ABSTRACT: Acute myeloid leukemia (AML) driven by the activation of EVI1 due to chromosome 3q26/MECOM rearrangements is incurable with current chemotherapy regimens. Insight into the mechanism by which EVI1 drives myeloid transformation is needed to target EVI1 in those leukemias. Here we demonstrate recurrent interaction of CTBP1/2 with a unique PLDLS motif in EVI1, which is indispensable for leukemic transformation of 3q26/MECOM rearranged AML. A PLDLS competitor construct outcompetes EVI1 to CTBP1/2 binding and inhibits AML proliferation in xenotransplant models. This proof-of-concept study opens the possibility to target one of the most incurable forms of AML using specific inhibitors directed to EVI1/CTBP1/2 interaction. Our findings have important implications for other tumour types with aberrant expression of EVI1 or other oncogenic transcription factors that also depend on CTBP1/2 interaction.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Jeroen Demmers

LAB HEAD: Jeroen Demmers

PROVIDER: PXD048760 | Pride | 2024-05-21

REPOSITORIES: Pride

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			Action	DRS
	2480_DorienPastoors_SN.xlsx	Xlsx
	2480_L_10Feb23_DorienPastoors_DIA_iRT_IP01_EVI1_A1.raw	Raw
	2480_L_10Feb23_DorienPastoors_DIA_iRT_IP02_EVI1_A2.raw	Raw
	2480_L_10Feb23_DorienPastoors_DIA_iRT_IP03_EVI1_B1.raw	Raw
	2480_L_10Feb23_DorienPastoors_DIA_iRT_IP04_EVI1_B2.raw	Raw

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Oncogene EVI1 drives acute myeloid leukemia via a targetable interaction with CTBP2.

Pastoors Dorien D Havermans Marije M Mulet-Lazaro Roger R Brian Duncan D Noort Willy W Grasel Julius J Hoogenboezem Remco R Smeenk Leonie L Demmers Jeroen A A JAA Milsom Michael D MD Enver Tariq T Groen Richard W J RWJ Bindels Eric E Delwel Ruud R

Science advances 20240515 20

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 indispen ...[more]

PMID: 38748792

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Project description:The MYB oncogene is widely expressed in acute leukemias and is important for the continued proliferation of leukemia cells, raising the possibility that MYB may be a therapeutic target. However realization of this potential requires (i) a significant therapeutic window for MYB inhibition, given its essential role in normal hematopoiesis; and (ii) an approach for developing an effective therapeutic. We previously showed that the interaction of Myb with the coactivator CBP/p300 is essential for its transforming activity. Here we use hematopoietic cells from the Booreana mouse strain, which carries a mutation in Myb that prevents interaction with CBP/p300, to examine the requirement for this interaction in myeloid transformation and leukemogenesis. Using this strain and a strain (plt6) carrying a “complementary” mutation in p300, we show that the Myb-p300 interaction is essential for in vitro transformation by the myeloid leukemia oncogenes AML1-ETO, AML1-ETO9a, MLL-ENL, and MLL-AF9. We further show that unlike cells from wild-type (WT) mice, Booreana cells fail to induce leukemia upon transplantation into irradiated recipients following transduction with an AML1-ETO9a retrovirus. These data highlight disruption of the Myb-p300 interaction as a potential therapeutic strategy for AML and suggest that such a strategy would have a useable therapeutic index since Booreana mice, unlike Myb null mice, are viable. Finally we have begun to explore the molecular basis of the these observations by gene expression profiling; this highlighted several genes previously implicated in myeloid leukemogenesis as being differentially expressed between WT and Booreana cells transduced with AML1-ETO9a. Total RNA was obtained from FACS sorted GFP+;c-Kit+ primary bone marrow cells from WT and Booreana mouse strains which had been cultured for 48 hours post-transduction with Control or AML1-ETO9a retroviruses. RNA was extracted from each of 4 samples per group and used to probe Illumina mouse Beadchips array.

Dataset Information

Oncogene EVI1 Drives Acute Myeloid Leukemia Via a Targetable Interaction with CTBP2

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Oncogene <i>EVI1</i> drives acute myeloid leukemia via a targetable interaction with CTBP2.

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