title: The oncogene EVI1 enhances transcriptional and biological responses of human myeloid cells to all-trans retinoic acid.
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 RARβ 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-β 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. The potential clinical implications of these findings are discussed.
authors.affiliation: a Department of Medicine I ; Medical University of Vienna ; Währinger Gürtel, Vienna , Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Steinmetz
authors.forename: Hubert
authors.initials: H
authors.lastname: Hackl
authors.forename: Eva
authors.initials: E
authors.lastname: Slabáková
authors.forename: Ilse
authors.initials: I
authors.lastname: Schwarzinger
authors.forename: Monika
authors.initials: M
authors.lastname: Smějová
authors.forename: Andreas
authors.initials: A
authors.lastname: Spittler
authors.forename: Itziar
authors.initials: I
authors.lastname: Arbesu
authors.forename: Medhat
authors.initials: M
authors.lastname: Shehata
authors.forename: Karel
authors.initials: K
authors.lastname: Souček
authors.forename: Rotraud
authors.initials: R
authors.lastname: Wieser
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques; D055436:Growth Differentiation Factor 15 / Q000235:genetics / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D000074008:MDS1 and EVI1 Complex Locus Protein; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism*; D009857:Oncogenes; D011519:Proto-Oncogenes / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D004268:DNA-Binding Proteins; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D014157:Transcription Factors; D014212:Tretinoin
keywords: AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; ATRA, all-trans retinoic acid; Ar, ATRA regulation; DMSO, dimethyl sulfoxide; EVI1; Em, EVI1 modulation; Er, EVI1 regulation; FBS, fetal bovine serum; FC, fold change; FDR, false discovery rate; GDF15; GFP, green fluorescent protein; MDS, myelodysplastic syndrome; PSG, penicillin streptomycin glutamine; RAR, retinoic acid receptor; RARE, retinoic acid response element; SE, standard error; all-trans retinoic acid; apoptosis; cell cycle; gene expression profiling; mcoEvi1, murine codon optimized Evi1; myeloid differentiation