Lentiviral vector common integration sites in preclinical models and a clinical trial reflect a benign integration bias and not oncogenic selection

Alessandra Biffi, Cynthia C. Bartholomae, Daniela Cesana, Natalie Cartier, Patrik Aubourg, Marco Ranzani, Martina Cesani, Fabrizio Benedicenti, Tiziana Plati, Enrico Rubagotti, Stefania Merella, Alessia Capotondo, Jacopo Sgualdino, Gianluigi Zanetti, Christof Von Kalle, Manfred Schmidt, Luigi Naldini, Eugenio Montini

Research output: Contribution to journalArticle

Abstract

A recent clinical trial for adrenoleukodystrophy (ALD) showed the efficacy and safety of lentiviral vector (LV) gene transfer in hematopoietic stem progenitor cells. However, several common insertion sites (CIS) were found in patients' cells, suggesting that LV integrations conferred a selective advantage. We performed highthroughput LV integration site analysis on human hematopoietic stem progenitor cells engrafted in immunodeficient mice and found the same CISs reported in patients with ALD. Strikingly, most CISs in our experimental model and in patients with ALD cluster in megabase-wide chromosomal regions of high LV integration density. Conversely, cancer-triggering integrations at CISs found in tumor cells from γretroviral vector-based clinical trials and oncogene-tagging screenings in mice always target a single gene and are contained in narrow genomic intervals. These findings imply that LV CISs are produced by an integration bias toward specific genomic regions rather than by oncogenic selection.

Original languageEnglish
Pages (from-to)5332-5339
Number of pages8
JournalBlood
Volume117
Issue number20
DOIs
Publication statusPublished - May 19 2011

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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    Biffi, A., Bartholomae, C. C., Cesana, D., Cartier, N., Aubourg, P., Ranzani, M., Cesani, M., Benedicenti, F., Plati, T., Rubagotti, E., Merella, S., Capotondo, A., Sgualdino, J., Zanetti, G., Von Kalle, C., Schmidt, M., Naldini, L., & Montini, E. (2011). Lentiviral vector common integration sites in preclinical models and a clinical trial reflect a benign integration bias and not oncogenic selection. Blood, 117(20), 5332-5339. https://doi.org/10.1182/blood-2010-09-306761