Resistance against Friend leukemia virus-induced leukemogenesis in DNA-dependent protein kinase (DNA-PK)-deficient scid mice associated with defective viral integration at the Spi-1 and Fli-1 site

Hasegawa, Maki; Yamaguchi, Shuichi; Aizawa, Shiro; Ikeda, Hidetoshi; Tatsumi, Kouichi; Noda, Yuko; Hirokawa, Katsuiku; Kitagawa, Masanobu

doi:10.1016/j.leukres.2005.01.016

« Previous Next »Leukemia Research
Volume 29, Issue 8 , Pages 933-942, August 2005

Resistance against Friend leukemia virus-induced leukemogenesis in DNA-dependent protein kinase (DNA-PK)-deficient scid mice associated with defective viral integration at the Spi-1 and Fli-1 site

Maki Hasegawa
- Department of Comprehensive Pathology, Aging and Developmental Sciences, Tokyo Medical and Dental University, Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 13-8519, Japan
Shuichi Yamaguchi
- Department of Comprehensive Pathology, Aging and Developmental Sciences, Tokyo Medical and Dental University, Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 13-8519, Japan
Shiro Aizawa
- Research Center for Radiation Safety, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan
Hidetoshi Ikeda
- Laboratory of Infectious Diseases, National Institute of Animal Health, 3-1-5 Kannondai, Tsukuba City, Ibaraki 305-0856, Japan
Kouichi Tatsumi
- Research Center for Radiation Safety, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan
Yuko Noda
- Research Center for Radiation Safety, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan
Katsuiku Hirokawa
- Department of Comprehensive Pathology, Aging and Developmental Sciences, Tokyo Medical and Dental University, Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 13-8519, Japan
Masanobu Kitagawa
- Department of Comprehensive Pathology, Aging and Developmental Sciences, Tokyo Medical and Dental University, Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 13-8519, Japan
- Corresponding author. Tel.: +81 3 5803 5399; fax: +81 3 5803 0123.

Received 5 October 2004; accepted 22 January 2005. published online 07 March 2011.

Abstract

Retroviral DNA integration is mediated by the viral protein integrase. However, elements of the host DNA repair machinery such as the phosphatidylinositol 3-kinase (PI-3K)-related protein kinase family system would play a role in the integration of viral DNA into the host DNA. Here, we show that a host PI-3K-related protein kinase, DNA-dependent protein kinase (DNA-PK), plays a role in the specific integration of retroviral DNA and induction of retroviral diseases in vivo. DNA-PK-deficient scid mice inoculated with Friend leukemia virus (FLV) exhibited a random integration into their genomic DNA and expressed the viral envelope protein gp70. However, the specific integration of FLV at Spi-1 or Fli-1 sites did not occur in association with the significant resistance of scid mice to FLV-induced leukemogenesis. In contrast, the knockout of another member of the PI-3K-related protein kinase family, encoded by the ataxia telangiectasia mutated (ATM) gene, resulted in mice as sensitive to FLV-induced leukemogenesis as the wild type mice. FLV was specifically integrated into the DNA at Spi-1 and Fli-1 sites with significant expression of these transcription factors. These findings indicated that DNA-PK would be essential for controlling the in vivo integration of FLV at specific sites as well as the susceptibility to FLV-induced leukemogenesis.

Keywords: Retrovirus infection, Friend virus, DNA-PK, ATM, Integration