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

Reba Condiotti, Daniel Goldenberg, Hilla Giladi, Temima Schnitzer-Perlman, Simon N. Waddington, Suzanne MK Buckley, Denise Heim, Wing Cheung, Matthew Themis, Charles Coutelle, Alina Simerzin, Emma Osejindu, Henning Wege, Michael Themis, Eithan Galun*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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.

Original languageAmerican English
Pages (from-to)59-68
Number of pages10
JournalMolecular Therapy
Volume22
Issue number1
DOIs
StatePublished - Jan 2014
Externally publishedYes

Bibliographical note

Funding Information:
We thank Assaf Bester and Batsheva Kerem from the Hebrew University, Jerusalem, Israel for common fragile sites data and helpful discussion, Ali Nowrouzi from the German Cancer Research Center, Heidelberg, Germany, and Alessandra Recchia from the University of Modena and Reggio Emilia, Modena, Italy for help with the inverse and LM-PCR pro- tocols and Aviezer Lifshitz for microRNA location analysis. This study was supported by ISF (E.G.), FP7 program LSHB-CT-2008-223317 (LIVES) (E.G.); the Kamea Scientific Foundation (D.G.); European Research Council grant "SomaBio" (S.M.K.B. and S.N.W.). Additional support was received from the Lillyan &Alfy Nathan (R.C.), Barbara Fox Miller, and Wolfson Foundations (E.G.). E.G. is part of the DFG SFB 841 program project. E.G. is supported by the I-CORE 41/11 ISF center of excellence center.

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