EVI1 in acute myeloid leukemia triggers metabolic reprogramming associated with leukemogenesis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE118096 | GEO | 2018/08/04
REPOSITORIES: GEO
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Project description:Chromosomal rearrangements involving EVI1 (MECOM) define a subtype of acute myeloid leukemia (AML) that is associated with a two-year survival rate of <10%. Gene regulatory functions of EVI1 are largely elusive and no targeted therapeutics exist. We developed experimentally tractable murine and human leukemia models that recapitulate phenotypic and transcriptional features of EVI1-rearranged AML and enable large-scale loss-of-function screens. We characterize EVI1-controlled transcriptional programs in cell culture and in vivo, perform CRISPR screens and identify the ETS-related transcription factor ERG as the only gene that is specifically required for EVI1-driven AML. ERG is transcriptionally activated by EVI1 and overexpressed in EVI1-rearranged AML patients. ERG suppression selectively induces terminal differentiation of leukemia cells. EVI1 becomes dispensable for leukemia cells upon ectopic expression of ERG, indicating that key functions of EVI1 are mediated through aberrant activation of ERG. Interfering with this regulatory axis may therefore provide new entry points for rational therapies.
2022-10-11 | GSE195497 | GEO
Project description:Ecotropic virus integration site 1 (EVI1), whose overexpression characterizes a particularly aggressive subtype of acute myeloid leukemia (AML), enhanced anti-leukemic activities of all-trans retinoic acid (atRA) in cell lines and patient samples. However, the drivers of leukemia formation, therapy resistance, and relapse are leukemic stem cells (LSCs), whose properties were hardly reflected in these experimental setups. The present study was designed to address the effects of, and interactions between, EVI1 and retinoids in AML LSCs. We report that Evi1 reduced the maturation of leukemic cells and promoted the abundance, quiescence, and activity of LSCs in an MLL-AF9-driven mouse model of AML. atRA further augmented these effects in an Evi1 dependent manner. EVI1 also strongly enhanced atRA regulated gene transcription in LSC enriched cells. One of their jointly regulated targets, Notch4, was an important mediator of their effects on leukemic stemness. In vitro exposure of leukemic cells to a pan-RAR antagonist caused effects opposite to those of atRA. In vivo antagonist treatment delayed leukemogenesis and reduced LSC abundance, quiescence, and activity in Evi1high AML. Key results were confirmed in human myeloid cell lines retaining some stem cell characteristics as well as in primary human AML samples. In summary, our study is the first to report the importance of EVI1 for key properties of AML LSCs. Furthermore, it shows that atRA enhances, and a pan-RAR antagonist counteracts, the effects of EVI1 on AML stemness, thus raising the possibility of using RAR antagonists in the therapy of EVI1high AML.
2019-12-13 | GSE123255 | GEO
Project description: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.
2024-05-21 | PXD048760 | Pride
Project description: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.
2023-07-13 | PXD043333 | Pride
Project description:Overexpression of the Ecotropic viral integration site 1 (EVI1) gene typically associates with aggressive forms of leukemia. Aberrant EVI1 expression is also detected in breast carcinoma but its role in this tumor type is largely unknown. In order to analyze its effects in breast cancer, shRNA knockdown was performed on MDA-MB-231 cells and gene expression compared in EVI1 knockdown versus corresponding control shRNA treated cells.
2017-02-24 | GSE95272 | GEO
Project description:Overexpression of ecotropic viral integration site 1 (EVI1) is associated with aggressive disease in acute myeloid leukemia (AML). Despite of its clinical importance, little is known about the mechanism through which EVI1 confers resistance to antileukemic drugs. Here, we show that a human myeloid cell line constitutively overexpressing EVI1 after infection with a retroviral vector (U937_EVI1) was partially resistant to etoposide and daunorubicin as compared to empty vector infected control cells (U937_vec). Similarly, inducible expression of EVI1 in HL-60 cells decreased their sensitivity to daunorubicin. Gene expression microarray analyses of U937_EVI1 and U937_vec cells cultured in the absence or presence of etoposide showed that 77 and 419 genes were regulated by EVI1 and etoposide, respectively. Notably, mRNA levels of 26 of these genes were altered by both stimuli, indicating that EVI1 regulated genes were strongly enriched among etoposide regulated genes and vice versa. One of the genes that were induced by both EVI1 and etoposide was CDKN1A/p21/WAF, which in addition to its function as a cell cycle regulator plays an important role in conferring chemotherapy resistance in various tumor types. Indeed, overexpression of CDKN1A in U937 cells mimicked the phenotype of EVI1 overexpression, similarly conferring partial resistance to antileukemic drugs. Rommer A, Steinmetz B, Herbst F, Hackl H, Heffeter P, Heilos D, Filipits M, Steinleitner K, Hemmati S, Herbacek I, Schwarzinger I, Hartl K, Rondou P, Glimm H, Karakaya K, Krämer A, Berger W, and Wieser R: EVI1 Inhibits Apoptosis Induced by Antileukemic Drugs via Upregulation of CDKN1A/p21/WAF in Human Myeloid Cells. PLoS One 8(2):e56308 (2013). doi: 10.1371/journal.pone.0056308. U937 cells transduced with an EVI1 expression vector or empty vector as control were treated or not with 400 nM etoposide for 48h. 2 biological replicate experiments were performed.
2015-03-10 | E-GEOD-66660 | biostudies-arrayexpress
Project description:We investigated the role of protein arginine methyltransferase 5 (PRMT5) in leukemia patient cells with inversion of chromosome 3. This rearrangement leads to overexpression of the proto-oncogene EVI1 (ecotropic virus integration site 1). To further investigate the mechanism of PRMT5 dependency in these cells, we performed transcriptome and splicing analyses.
2022-03-23 | GSE163305 | GEO
Project description:The overexpression of the ecotropic viral integration site-1 gene (EVI1/MECOM) marks the most lethal acute myeloid leukemia (AML) subgroup carrying chromosome 3q26 abnormalities. By taking advantage of the intersectionality of high-throughput cell-based and gene expression screens, we identified selective and pan-histone deacetylase inhibitors (HDACis) as potent repressors of EVI1. To understand the mechanism driving on-target anti-leukemia activity of this compound class, we dissected the expression dynamics of the bone marrow leukemia cells of patients treated with HDACi and reconstituted the EVI1 chromatin-associated co-transcriptional complex merging on the role of proliferation-associated 2G4 protein. PA2G4 overexpression rescues AML cells from the inhibitory effects of HDACis, while genetic and small molecule inhibition of PA2G4 abrogated EVI1 in 3q26 AML cells, including in patient-derived leukemia xenografts. This study positions PA2G4 at the crosstalk of the EVI1 leukemogenic signal for developing new therapeutics and urges the use of HDACi-based combination therapies in patients with 3q26 AML.
2024-04-01 | GSE259221 | GEO
Project description:The overexpression of the ecotropic viral integration site-1 gene (EVI1/MECOM) marks the most lethal acute myeloid leukemia (AML) subgroup carrying chromosome 3q26 abnormalities. By taking advantage of the intersectionality of high-throughput cell-based and gene expression screens, we identified selective and pan-histone deacetylase inhibitors (HDACis) as potent repressors of EVI1. To understand the mechanism driving on-target anti-leukemia activity of this compound class, we dissected the expression dynamics of the bone marrow leukemia cells of patients treated with HDACi and reconstituted the EVI1 chromatin-associated co-transcriptional complex merging on the role of proliferation-associated 2G4 protein. PA2G4 overexpression rescues AML cells from the inhibitory effects of HDACis, while genetic and small molecule inhibition of PA2G4 abrogated EVI1 in 3q26 AML cells, including in patient-derived leukemia xenografts. This study positions PA2G4 at the crosstalk of the EVI1 leukemogenic signal for developing new therapeutics and urges the use of HDACi-based combination therapies in patients with 3q26 AML.
2024-04-01 | GSE256130 | GEO
Project description:The overexpression of the ecotropic viral integration site-1 gene (EVI1/MECOM) marks the most lethal acute myeloid leukemia (AML) subgroup carrying chromosome 3q26 abnormalities. By taking advantage of the intersectionality of high-throughput cell-based and gene expression screens, we identified selective and pan-histone deacetylase inhibitors (HDACis) as potent repressors of EVI1. To understand the mechanism driving on-target anti-leukemia activity of this compound class, we dissected the expression dynamics of the bone marrow leukemia cells of patients treated with HDACi and reconstituted the EVI1 chromatin-associated co-transcriptional complex merging on the role of proliferation-associated 2G4 protein. PA2G4 overexpression rescues AML cells from the inhibitory effects of HDACis, while genetic and small molecule inhibition of PA2G4 abrogated EVI1 in 3q26 AML cells, including in patient-derived leukemia xenografts. This study positions PA2G4 at the crosstalk of the EVI1 leukemogenic signal for developing new therapeutics and urges the use of HDACi-based combination therapies in patients with 3q26 AML.
2024-04-01 | GSE256129 | GEO