title: Transduction of fetal mice with a feline lentiviral vector induces liver tumors which exhibit an E2F activation signature.
abstract: Lentiviral vectors are widely used in basic research and clinical applications for gene transfer and long-term expression; however, safety issues have not yet been completely resolved. In this study, we characterized hepatocarcinomas that developed in mice 1 year after in utero administration of a feline-derived lentiviral vector. Mapped viral integration sites differed among tumors and did not coincide with the regions of chromosomal aberrations. Furthermore, gene expression profiling revealed that no known cancer-associated genes were deregulated in the vicinity of viral integrations. Nevertheless, five of the six tumors exhibited highly significant upregulation of E2F target genes, of which a majority are associated with oncogenesis, DNA damage response, and chromosomal instability. We further show in vivo and in vitro that E2F activation occurs early on following transduction of both fetal mice and cultured human hepatocytes. On the basis of the similarities in E2F target gene expression patterns among tumors and the lack of evidence implicating insertional mutagenesis, we propose that transduction of fetal mice with a feline lentiviral vector induces E2F-mediated major cellular processes that drive hepatocytes toward uncontrolled proliferation culminating in tumorigenesis.
authors: Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors: Reba
authors: R
authors: Condiotti
authors: Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors: Daniel
authors: D
authors: Goldenberg
authors: Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors: Hilla
authors: H
authors: Giladi
authors: Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors: Temima
authors: T
authors: Schnitzer-Perlman
authors: 1] Institute for Women's Health, University College London, London, UK [2] School of Pathology, University of the Witwatersrand, Johannesburg, South Africa.
authors: Simon N
authors: SN
authors: Waddington
authors: Department of Haematology, University College Medical School, London, UK.
authors: Suzanne Mk
authors: SM
authors: Buckley
authors: Department of Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Denise
authors: D
authors: Heim
authors: Institute for Women's Health, University College London, London, UK.
authors: Wing
authors: W
authors: Cheung
authors: Division of Biosciences, Brunel University, Middlesex, UK.
authors: Matthew
authors: M
authors: Themis
authors: Gene Therapy Research Group, Imperial College, London, UK.
authors: Charles
authors: C
authors: Coutelle
authors: Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors: Alina
authors: A
authors: Simerzin
authors: Division of Biosciences, Brunel University, Middlesex, UK.
authors: Emma
authors: E
authors: Osejindu
authors: Department of Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Henning
authors: H
authors: Wege
authors: 1] Division of Biosciences, Brunel University, Middlesex, UK [2] National Heart and Lung Institute, Imperial College, London, UK.
authors: Michael
authors: M
authors: Themis
authors: Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors: Eithan
authors: E
authors: Galun
mesh_terms: D000818:Animals; D002415:Cats; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002869:Chromosome Aberrations; D004249:DNA Damage; D050684:E2F Transcription Factors / Q000378:metabolism*; D005333:Fetus; D018628:Gene Dosage; D015870:Gene Expression; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D017969:Lentiviruses, Feline / Q000235:genetics*; D008113:Liver Neoplasms / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D016254:Mutagenesis, Insertional; D059467:Transcriptome; D014161:Transduction, Genetic; D019076:Transgenes; D016662:Virus Integration
chemical_list: D050684:E2F Transcription Factors
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