TY - JOUR
T1 - Hot spots of retroviral integration in human CD34+ hematopoietic cells
AU - Cattoglio, Claudia
AU - Facchini, Giulia
AU - Sartori, Daniela
AU - Antonelli, Antonella
AU - Miccio, Annarita
AU - Cassani, Barbara
AU - Schmidt, Manfred
AU - Von Kalle, Christof
AU - Howe, Steve
AU - Thrasher, Adrian J.
AU - Aiuti, Alessandro
AU - Ferrari, Giuliana
AU - Recchia, Alessandra
AU - Mavilio, Fulvio
PY - 2007/9/15
Y1 - 2007/9/15
N2 - Insertional oncogenesis is a possible consequence of the integration of gammaretroviral (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.
AB - Insertional oncogenesis is a possible consequence of the integration of gammaretroviral (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.
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U2 - 10.1182/blood-2007-01-068759
DO - 10.1182/blood-2007-01-068759
M3 - Article
C2 - 17507662
AN - SCOPUS:34547657665
VL - 110
SP - 1770
EP - 1778
JO - Blood
JF - Blood
SN - 0006-4971
IS - 6
ER -