title: Identification of a high incidence region for retroviral vector integration near exon 1 of the LMO2 locus.
abstract: Therapeutic retroviral vector integration near the oncogene LMO2 is thought to be a cause of leukemia in X-SCID gene therapy trials. However, no published studies have evaluated the frequency of vector integrations near exon 1 of the LMO2 locus. We identified a high incidence region (HIR) of vector integration using PCR techniques in the upstream region close to the LMO2 transcription start site in the TPA-Mat T cell line. The integration frequency of the HIR was one per 4.46 x 10(4) cells. This HIR was also found in Jurkat T cells but was absent from HeLa cells. Furthermore, using human cord blood-derived CD34+ cells we identified a HIR in a similar region as the TPA-Mat T cell line. One of the X-linked severe combined immunodeficiency (X-SCID) patients that developed leukemia after gene therapy had a vector integration site in this HIR. Therefore, the descriptions of the location and the integration frequency of the HIR presented here may help us to better understand vector-induced leukemogenesis.
authors.affiliation: Department of Microbiology and Immunology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan. koichiro@shinshu-u.ac.jp
authors.forename: Koichiro
authors.initials: K
authors.lastname: Yamada
authors.forename: Tomonori
authors.initials: T
authors.lastname: Tsukahara
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Yoshino
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Kojima
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Agawa
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Yuji
authors.initials: Y
authors.lastname: Amano
authors.forename: Mariko
authors.initials: M
authors.lastname: Hatta
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Matsuzaki
authors.forename: Naoki
authors.initials: N
authors.lastname: Kurotori
authors.forename: Keiko
authors.initials: K
authors.lastname: Wakui
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Fukushima
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Osada
authors.forename: Tanri
authors.initials: T
authors.lastname: Shiozawa
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sakashita
authors.forename: Kenichi
authors.initials: K
authors.lastname: Koike
authors.forename: Satoru
authors.initials: S
authors.lastname: Kumaki
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Takeshita
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D060588:LIM Domain Proteins; D008667:Metalloproteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins; D012190:Retroviridae / Q000502:physiology*; D013601:T-Lymphocytes / Q000821:virology*; D016662:Virus Integration
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; D008667:Metalloproteins; D011518:Proto-Oncogene Proteins