title: Hot spots of retroviral integration in human CD34+ hematopoietic cells.
abstract: 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 (CISs) have been identified in hematopoietic malignancies and in the nonmalignant 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 more than 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 CISs, 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 nontransplanted 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.
authors.affiliation: Italian Institute of Technology, Unit of Molecular Neuroscience, Istituto Scientifico H. San Raffaele, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cattoglio
authors.forename: Giulia
authors.initials: G
authors.lastname: Facchini
authors.forename: Daniela
authors.initials: D
authors.lastname: Sartori
authors.forename: Antonella
authors.initials: A
authors.lastname: Antonelli
authors.forename: Annarita
authors.initials: A
authors.lastname: Miccio
authors.forename: Barbara
authors.initials: B
authors.lastname: Cassani
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmidt
authors.forename: Christof
authors.initials: C
authors.lastname: von Kalle
authors.forename: Steve
authors.initials: S
authors.lastname: Howe
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aiuti
authors.forename: Giuliana
authors.initials: G
authors.lastname: Ferrari
authors.forename: Alessandra
authors.initials: A
authors.lastname: Recchia
authors.forename: Fulvio
authors.initials: F
authors.lastname: Mavilio
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D017988:Gammaretrovirus / Q000502:physiology*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000821:virology*; D006801:Humans; D016086:Lentivirus / Q000502:physiology; D016254:Mutagenesis, Insertional; D009363:Neoplasm Proteins / Q000235:genetics*; D011995:Recombination, Genetic; D012190:Retroviridae / Q000235:genetics*; D014161:Transduction, Genetic; D014162:Transfection; D016662:Virus Integration / Q000235:genetics*
chemical_list: D018952:Antigens, CD34; D009363:Neoplasm Proteins