1. Lentiviral vector common integration sites in preclinical models and a clinical trial reflect a benign integration bias and not oncogenic selection
- Author
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Stefania Merella, Gianluigi Zanetti, Martina Cesani, Cynthia C. Bartolomae, Daniela Cesana, Alessia Capotondo, Jacopo Sgualdino, Tiziana Plati, Natalie Cartier, Patrik Aubourg, Christof von Kalle, Luigi Naldini, Eugenio Montini, Enrico Rubagotti, Manfred G. Schmidt, Fabrizio Benedicenti, Alessandra Biffi, Marco Ranzani, Biffi, A, Bartolomae, Cc, 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, Luigi, and Montini, E.
- Subjects
Knockout ,Virus Integration ,medicine.medical_treatment ,Genetic Vectors ,Immunology ,Hematopoietic stem cell transplantation ,medicine.disease_cause ,Biochemistry ,Viral vector ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Adrenoleukodystrophy ,Animals ,Clinical Trials as Topic ,DNA-Binding Proteins ,Gene Transfer Techniques ,Genetic Therapy ,Hematopoietic Stem Cell Transplantation ,Humans ,Interleukin Receptor Common gamma Subunit ,Lentivirus ,Mice, Knockout ,Transplantation Chimera ,Progenitor cell ,Gene ,030304 developmental biology ,0303 health sciences ,business.industry ,Cell Biology ,Hematology ,Transplantation ,Haematopoiesis ,030220 oncology & carcinogenesis ,Cancer research ,Stem cell ,Carcinogenesis ,business - 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.
- Published
- 2011