Self-inactivating retroviral vector-mediated gene transfer induces oncogene activation and immortalization of primary murine bone marrow cells

Marita Bosticardo, Amrita Ghosh, Yang Du, Nancy A. Jenkins, Neal G. Copeland, Fabio Candotti

Research output: Contribution to journalArticle

Abstract

Insertional mutagenesis leading to insurgence of leukemia has been shown as a consequence of retroviral (RV)-mediated gene transfer in animal models and in clinical trials of gene therapy for X-linked severe combined immunodeficiency. Aberrant expression of oncogenes neighboring the γ-RV vector insertion site via induction by the enhancer element of the viral long terminal repeats (LTRs) is thought to have played a role in leukemogenesis. Consequently, RV vectors devoid of LTR enhancer elements could prove as safer tools for gene transfer. To test this hypothesis, we evaluated the immortalization ability of two RV vectors: one carrying the full-length Moloney leukemia virus (MLV) LTR and one with the same LTR in which the enhancer element was deleted [MLV self-inactivating (SIN)]. Unexpectedly, transduction with MLV SIN resulted in an only slightly and not significant decreased immortalization frequency of primary bone marrow (BM) cultures (about 37%) compared to transduction with MLV (about 48%). Similar to MLV, immortalization by MLV SIN is likely caused by insertional activation of oncogenes including Evi1, Mds1, Mef2c, and Hoxa7. Our results indicate that the MLV SIN, devoid of the LTR enhancer element, was still able to immortalize BM cells by activating nearby gene expression, indicating the need of an accurate selection of the internal promoter to obtain safer SIN RV vectors.

Original languageEnglish
Pages (from-to)1910-1918
Number of pages9
JournalMolecular Therapy
Volume17
Issue number11
DOIs
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

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