Identification of a high incidence region for retroviral vector integration near exon 1 of the LMO2 locus.
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.
Yamada
Koichiro
K
Department of Microbiology and Immunology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan. koichiro@shinshu-u.ac.jp
Tsukahara
Tomonori
T
Yoshino
Kazuhisa
K
Kojima
Katsuhiko
K
Agawa
Hideyuki
H
Yamashita
Yuki
Y
Amano
Yuji
Y
Hatta
Mariko
M
Matsuzaki
Yasunori
Y
Kurotori
Naoki
N
Wakui
Keiko
K
Fukushima
Yoshimitsu
Y
Osada
Ryosuke
R
Shiozawa
Tanri
T
Sakashita
Kazuo
K
Koike
Kenichi
K
Kumaki
Satoru
S
Tanaka
Nobuyuki
N
Takeshita
Toshikazu
T
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
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; D008667:Metalloproteins; D011518:Proto-Oncogene Proteins