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The oncogene EVI1 enhances transcriptional and biological responses of human myeloid cells to all-trans retinoic acid [HL60]

ABSTRACT: The product of the ecotropic virus integration site 1 (EVI1) gene, whose overexpression is associated with a poor prognosis in myeloid leukemias and some epithelial tumors, regulates gene transcription both through direct DNA binding and through modulation of the activity of other sequence specific transcription factors. Previous results from our laboratory have shown that EVI1 influenced transcription regulation in response to the myeloid differentiation inducing agent, all-trans retinoic acid (ATRA), in a dual manner: it enhanced ATRA induced transcription of the RARb gene, but repressed the ATRA induction of the EVI1 gene itself. In the present study, we asked whether EVI1 would modulate the ATRA regulation of a larger number of genes, as well as biological responses to this agent, in human myeloid cells. U937 and HL-60 cells ectopically expressing EVI1 through retroviral transduction were subjected to microarray based gene expression analysis, and to assays measuring cellular proliferation, differentiation, and apoptosis. These experiments showed that EVI1 modulated the ATRA response of several dozens of genes, and in fact reinforced it in the vast majority of cases. A particularly strong synergy between EVI1 and ATRA was observed for GDF15, which codes for a member of the TGF-b superfamily of cytokines. In line with the gene expression results, EVI1 enhanced cell cycle arrest, differentiation, and apoptosis in response to ATRA, and knockdown of GDF15 counteracted some of these effects.

ORGANISM(S): Homo sapiens

PROVIDER: GSE66837 | GEO | 2015/03/13

SECONDARY ACCESSION(S): PRJNA278064

REPOSITORIES: GEO

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The oncogene EVI1 enhances transcriptional and biological responses of human myeloid cells to all-trans retinoic acid [U937]

Project description:The product of the ecotropic virus integration site 1 (EVI1) gene, whose overexpression is associated with a poor prognosis in myeloid leukemias and some epithelial tumors, regulates gene transcription both through direct DNA binding and through modulation of the activity of other sequence specific transcription factors. Previous results from our laboratory have shown that EVI1 influenced transcription regulation in response to the myeloid differentiation inducing agent, all-trans retinoic acid (ATRA), in a dual manner: it enhanced ATRA induced transcription of the RARb gene, but repressed the ATRA induction of the EVI1 gene itself. In the present study, we asked whether EVI1 would modulate the ATRA regulation of a larger number of genes, as well as biological responses to this agent, in human myeloid cells. U937 and HL-60 cells ectopically expressing EVI1 through retroviral transduction were subjected to microarray based gene expression analysis, and to assays measuring cellular proliferation, differentiation, and apoptosis. These experiments showed that EVI1 modulated the ATRA response of several dozens of genes, and in fact reinforced it in the vast majority of cases. A particularly strong synergy between EVI1 and ATRA was observed for GDF15, which codes for a member of the TGF-b superfamily of cytokines. In line with the gene expression results, EVI1 enhanced cell cycle arrest, differentiation, and apoptosis in response to ATRA, and knockdown of GDF15 counteracted some of these effects. Steinmetz B, Hackl H, Slabáková E, Schwarzinger I, Smějová M, Spittler A, Arbesu I, Shehata M, Souček K, and Wieser R: The oncogene EVI1 enhances transcriptional and biological responses of human myeloid cells to all-trans retinoic acid. Cell Cycle 13, 2931-2943 (2014).

2015-03-13 | GSE66854 | GEO

All-trans retinoic acid enhances, and a pan-RAR antagonist counteracts, the stem cell promoting activity of EVI1 in acute myeloid leukemia

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

EVI1 in acute myeloid leukemia triggers metabolic reprogramming associated with leukemogenesis

Project description:Overexpression of Ecotropic Virus Integration site 1 protein homolog (EVI1) in adults and children with mixed lineage leukemia-rearrangement acute myeloid leukemia (MLL-r AML) has a very poor prognosis. We used an extracellular flux analyze to examine metabolic changes during leukemia development in a mouse model of MLL-r AML expressing high levels of Evi1 (Evi1+).

2018-08-04 | GSE118096 | GEO

Gene expression changes in U937 cells in response to ectopic expression of EVI1 and/or etoposide treatment

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

Evi1 governs Kdm6b-mediated histone demethylation to finely regulate the Laptm4b-driven mTORC pathway in vivo [LSK]

Project description:Ecotropic viral integration site 1 (EVI1/MECOM) overexpression is common in myeloid malignancies. We present a new Evi1 transgenic mouse model with inducible expression in hematopoietic stem cells (HSCs) and progenitor cells (HPCs) at lower levels. Upon exogenous Evi1 induction, mice displayed anemia, thrombocytopenia, lymphopenia, and dysplasia in erythroid and megakaryocyte cells with a significant expansion of committed myeloid progenitor cells, resembling human Myelodysplastic syndrome/Myeloproliferative neoplasm (MDS/MPN)-like disease. Methods: LSK cells were sorted by Sony SH800 from 3 pairs of mice transplanted with WT BM cells and Evi1-OE BM cells after pIpC injection. Around 5X103 LSK cells were harvested from each mouse. Then the cells were lysated by Trizol and total RNA was extracted by phenol-chloroform. Results: Molecular pathways altered in LSK cells from recipient mice transplanted with Evi1-OE BM cells. Conclusions: Transcription profile changed in Evi1 overexpressing hematopoietic stem and progenitor cells.

2023-06-27 | GSE235441 | GEO

Evi1 governs Kdm6b-mediated histone demethylation to finely regulate the Laptm4b-driven mTORC pathway in vivo [LK]

Project description:Ecotropic viral integration site 1 (EVI1/MECOM) overexpression is common in myeloid malignancies. We present a new Evi1 transgenic mouse model with inducible expression in hematopoietic stem cells (HSCs) and progenitor cells (HPCs) at lower levels. Upon exogenous Evi1 induction, mice displayed anemia, thrombocytopenia, lymphopenia, and dysplasia in erythroid and megakaryocyte cells with a significant expansion of committed myeloid progenitor cells, resembling human Myelodysplastic syndrome/Myeloproliferative neoplasm (MDS/MPN)-like disease. Methods: Lin-C-Kit+ cells were isolated from 3 pairs of WT and Evi1 overexpressing mice. Around 1X106 Lin-C-Kit+ cells were harvested from each mouse. Then the cells were lysated by Trizol and total RNA was extracted by phenol-chloroform. Results: Molecular pathways altered in Lin-C-Kit+ cells from Evi1-OE mice. Conclusions: Multiple molecular pathways changed in Evi1 overexpressing hematopoietic stem and progenitor cells.

2023-06-27 | GSE235440 | GEO

Genome-wide identification of binding sites of Evi1 in human myeloid cell lines

Project description:The EVI1 gene codes for a transcription factor with important roles in development and leukemogenesis. Overexpression of EVI1 in acute myeloid leukemia (AML) is one of the worst prognostic factors in patients with and without 3q26 rearrangements. Evi1 acts in several pathways through the interaction with proteins with important functions in hematopoiesis; however, the role of Evi1 as a transcription factor is not well known, and only some Evi1 target genes have been identified in mice. Our aim was to investigate the pathways and direct target genes of EVI1. Differential expression profiles after EVI1 knockdown allowed us to identify 125 genes involved in cell growth, differentiation and signal transduction that could be related to EVI1. Moreover, we looked for potential EVI1 binding sites within the region 1000 bp upstream of the transcription start sites of all human genes. We selected a total of 70 genes from the bioinformatics search, genes related to EVI1 by literature, and genes differentially expressed in the expression array. ChIP in the TF1 and HEL cell lines with two EVI1 antibodies demonstrated that EVI1 binds to the proximal promoter regions of 18 of these genes, most of them involved in important differentiation and proliferation pathways, confirming the important role of EVI1. Interestingly, EVI1 binds to the proximal region of its promoter, suggesting that it could be regulating its own transcription. Further functional studies are in progress. These data provide a starting point for further studies aimed at uncovering the mechanism for EVI1-induced transformation leukemias. Keywords: Gene expression analysis after transient knockdown of EVI1. 12 samples. Three replicates per experimental condition. Two cell lines (HTB-58, TF-1). Transient EVI1 knockdown using anti-EVI1 siRNA molecules vs. control siRNA.

2012-09-30 | E-GEOD-16238 | biostudies-arrayexpress

Gene expression changes in U937 cells in response to ectopic expression of EVI1 and/or etoposide treatment

2015-03-10 | GSE66660 | GEO

Prominent oncogenic roles of EVI1 in breast carcinoma

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

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

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

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