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Blood, 15 September 2007, Vol. 110, No. 6, pp. 1770-1778.
Prepublished online as a Blood First Edition Paper on May 16, 2007; DOI 10.1182/blood-2007-01-068759.
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Submitted January 26, 2007
Accepted May 10, 2007
Hot spots of retroviral integration in human CD34+ hematopoietic cells
Claudia Cattoglio, Giulia Facchini, Daniela Sartori, Antonella Antonelli, Annarita Miccio, Barbara Cassani, Manfred Schmidt, Christof von Kalle, Steve Howe, Adrian J. Thrasher, Alessandro Aiuti, Giuliana Ferrari, Alessandra Recchia, and Fulvio Mavilio*
IIT Unit of Molecular Neuroscience, Istituto Scientifico H. San Raffaele, Milan, Italy
Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy
HSR-TIGET, Istituto Scientifico H. San Raffaele, Milan, Italy
National Center for Tumor Diseases, Heidelberg, Germany
Molecular Immunology Unit, Institute of Child Health, London, United Kingdom
Vita-Salute San Raffaele University, Milan, Italy
* Corresponding author; email: fulvio.mavilio{at}unimore.it.
Insertional oncogenesis is a possible consequence of the integration of gamma-retroviral (RV) or lentiviral (LV) vectors into the human genome. RV common insertion sites (CIS) have been identified in hematopoietic malignancies and in the non-malignant progeny of transduced hematopoietic stem/progenitor cells (HSCs), possibly as a consequence of clonal selection in vivo. We have mapped a large number of RV and LV integrations in human CD34+ HSCs, transduced in vitro and analyzed without selection. Recurrent insertion sites (hot spots) account for >21% of the RV integration events, while they are significantly less frequent in the case of LV vectors. RV but not LV hot spots are highly enriched in proto-oncogenes, cancer-associated CIS, and growth-controlling genes, indicating that at least part of the biases observed in the HSC progeny in vivo are characteristics of RV integration, already present in non-transplanted cells. Genes involved in hematopoietic and immune system development are targeted at high frequency and enriched in hot spots, suggesting that the CD34+ gene expression program is instrumental in directing RV integration. The lower propensity of LV vectors for integrating in potentially dangerous regions of the human genome may be a factor determining a better safety profile for gene therapy applications.
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