Hanai Shuji, Nitta Takayuki, Shoda Momoko, Tanaka Masakazu, Iso Naomi, Mizoguchi Izuru, Yashiki Shinji, Sonoda Shunro, Hasegawa Yuichi, Nagasawa Toshiro, Miwa Masanao
Department of Biochemistry and Molecular Oncology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki 305-8575, Japan.
Cancer Sci. 2004 Apr;95(4):306-10. doi: 10.1111/j.1349-7006.2004.tb03207.x.
Adult T-cell leukemia (ATL) occurs after a long latent period of persistent infection by human T-cell leukemia virus type 1 (HTLV-1). However, the mechanism of oncogenesis by HTLV-1 remains to be clarified. It was reported that the incidence curve of ATL versus age was consistent with a multistage carcinogenesis model. Although HTLV-1 is an oncogenic retrovirus, a mechanism of carcinogenesis in ATL by insertional mutagenesis as one step during multistage carcinogenesis has not been considered thus far, because the exact integration sites on the chromosome have not been analyzed. Here we determined the precise HTLV-1 integration sites on the human chromosome, by taking advantage of the recently available human genome database. We isolated 25 integration sites of HTLV-1 from 23 cases of ATL. Interestingly, 13 (52%) of the integration sites were within genes, a rate significantly higher than that expected in the case of random integration (P = 0.043, chi(2) test). These results suggest that preferential integration into genes at the first infection is a characteristic of HTLV-1. However considering that some of the genes are related to the regulation of cell growth, the integration of HTLV-1 into or near growth-related genes might contribute to the clonal selection of HTLV-1-infected cells during multistage carcinogenesis of ATL.
成人T细胞白血病（ATL）在人类T细胞白血病病毒1型（HTLV-1）持续感染的长期潜伏期后发生。然而，HTLV-1的致癌机制仍有待阐明。据报道，ATL发病率与年龄的曲线符合多阶段致癌模型。尽管HTLV-1是一种致癌逆转录病毒，但迄今为止，尚未考虑在多阶段致癌过程中作为一个步骤的插入诱变导致ATL致癌的机制，因为尚未分析染色体上的确切整合位点。在此，我们利用最近可获得的人类基因组数据库，确定了人类染色体上HTLV-1的精确整合位点。我们从23例ATL病例中分离出25个HTLV-1整合位点。有趣的是，13个（52%）整合位点位于基因内，这一比例显著高于随机整合情况下预期的比例（P = 0.043，卡方检验）。这些结果表明，首次感染时优先整合到基因中是HTLV-1的一个特征。然而，考虑到一些基因与细胞生长调节有关，HTLV-1整合到生长相关基因内或其附近可能在ATL的多阶段致癌过程中有助于HTLV-1感染细胞的克隆选择。
