title: Fragile sites are preferential targets for integrations of MLV vectors in gene therapy.
abstract: Following gene therapy of SCID-X1 using murine leukemia virus (MLV) derived vector, two patients developed leukemia owing to an activating vector integration near the LMO2 gene. We found that these integrations reside within FRA11E, a common fragile site known to correlate with chromosomal breakpoints in tumors. Further analysis showed that fragile sites attract a nonrandom number of MLV integrations, shedding light on its integration mechanism and risk-to-benefit ratio in gene therapy.
authors.affiliation: Department of Genetics, Silberman Life Sciences Institute, Hebrew University, Jerusalem, Israel.
authors.forename: A C
authors.initials: AC
authors.lastname: Bester
authors.forename: M
authors.initials: M
authors.lastname: Schwartz
authors.forename: M
authors.initials: M
authors.lastname: Schmidt
authors.forename: A
authors.initials: A
authors.lastname: Garrigue
authors.forename: S
authors.initials: S
authors.lastname: Hacein-Bey-Abina
authors.forename: M
authors.initials: M
authors.lastname: Cavazzana-Calvo
authors.forename: N
authors.initials: N
authors.lastname: Ben-Porat
authors.forename: C
authors.initials: C
authors.lastname: Von Kalle
authors.forename: A
authors.initials: A
authors.lastname: Fischer
authors.forename: B
authors.initials: B
authors.lastname: Kerem
mesh_terms: D002478:Cells, Cultured; D043283:Chromosome Fragile Sites; D002873:Chromosome Fragility; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods; D005822:Genetic Vectors / Q000009:adverse effects* / Q000235:genetics; D006367:HeLa Cells / Q000821:virology; D006801:Humans; D007938:Leukemia / Q000276:immunology / Q000821:virology; D009052:Leukemia Virus, Murine / Q000235:genetics*; D016254:Mutagenesis, Insertional; D018570:Risk Assessment; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000821:virology; D016662:Virus Integration / Q000235:genetics*