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Mol Ther. 2014 Jan;22(1):59-68. doi: 10.1038/mt.2013.193. Epub 2013 Aug 28.

Transduction of fetal mice with a feline lentiviral vector induces liver tumors which exhibit an E2F activation signature.

Author information

1
Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
2
1] Institute for Women's Health, University College London, London, UK [2] School of Pathology, University of the Witwatersrand, Johannesburg, South Africa.
3
Department of Haematology, University College Medical School, London, UK.
4
Department of Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
5
Institute for Women's Health, University College London, London, UK.
6
Division of Biosciences, Brunel University, Middlesex, UK.
7
Gene Therapy Research Group, Imperial College, London, UK.
8
1] Division of Biosciences, Brunel University, Middlesex, UK [2] National Heart and Lung Institute, Imperial College, London, UK.

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.

PMID:
23982166
PMCID:
PMC3978808
DOI:
10.1038/mt.2013.193
[Indexed for MEDLINE]
Free PMC Article
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