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

Biffi, Alessandra, Bartolomae, Cynthia C., Cesana, Daniela, Cartier, Natalie, Aubourg, Patrik, Ranzani, Marco, Cesani, Martina, Benedicenti, Fabrizio, Plati, Tiziana, Rubagotti, Enrico, Merella, Stefania, Capotondo, Alessia, Sgualdino, Jacopo, Zanetti, Gianluigi, von Kalle, Christof, Schmidt, Manfred, Naldini, Luigi, Montini, Eugenio·2011·Blood
DOI 10.1182/blood-2010-09-306761
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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 high-throughput 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.

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Cited by

Metadata

Authors
Biffi, A., Bartolomae, 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.
Affiliations
  • San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy;
  • National Center for Tumor Diseases, Heidelberg, Germany;
  • Inserm UMR745, University Paris-Descartes, Paris, France; and
  • Distributed Computing Group, Center for Advanced Studies, Research, and Development in Sardinia (CRS4), Pula, Italy
Venue
Blood
Publisher
American Society of Hematology
Published
2011-05-19
Volume
117
Issue
20
Pages
5332-5339
ISSN
  • 0006-4971
  • 1528-0020
DOI
10.1182/blood-2010-09-306761
Cited by
216
References
4
Language
en

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