title: EVI1 inhibits apoptosis induced by antileukemic drugs via upregulation of CDKN1A/p21/WAF in human myeloid cells.
abstract: 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.
authors: Department of Medicine I, Medical University of Vienna, Vienna, Austria.
authors: Anna
authors: A
authors: Rommer
authors: Birgit
authors: B
authors: Steinmetz
authors: Friederike
authors: F
authors: Herbst
authors: Hubert
authors: H
authors: Hackl
authors: Petra
authors: P
authors: Heffeter
authors: Daniela
authors: D
authors: Heilos
authors: Martin
authors: M
authors: Filipits
authors: Katarina
authors: K
authors: Steinleitner
authors: Shayda
authors: S
authors: Hemmati
authors: Irene
authors: I
authors: Herbacek
authors: Ilse
authors: I
authors: Schwarzinger
authors: Katharina
authors: K
authors: Hartl
authors: Pieter
authors: P
authors: Rondou
authors: Hanno
authors: H
authors: Glimm
authors: Kadin
authors: K
authors: Karakaya
authors: Alwin
authors: A
authors: Krämer
authors: Walter
authors: W
authors: Berger
authors: Rotraud
authors: R
authors: Wieser
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003630:Daunorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D022423:Myeloid Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011519:Proto-Oncogenes / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D014157:Transcription Factors; D005047:Etoposide; D003630:Daunorubicin