Preferential selection of human T-cell leukemia virus type I provirus integration sites in leukemic versus carrier states
Preferential selection of human T-cell leukemia virus type I provirus integration sites in leukemic versus carrier states
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DOI：
10.1182/blood-2004-11-4350
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发表时间：
2005-08-01
期刊：
影响因子：
20.3
通讯作者：
Matsuoka, M
中科院分区：
文献类型：
--
作者：
Doi, K;Wu, XL;Matsuoka, M
人类T细胞白血病病毒I型（HTLV-1）是肿瘤性疾病成人T细胞白血病（ATL）的病原体。虽然编码病毒蛋白在肿瘤发生中起重要作用，但HTLV-1前病毒整合位点的作用仍然未解决。我们确定了HTLV-1前病毒在ATL细胞和HTLV-1感染细胞中的整合位点。在携带者和ATL细胞中，HTLV-1前病毒整合到转录单位中的频率分别为26.8%（15/56）和33.9%（20/59），这与基于随机整合计算的频率（33.2%）相当。此外，HTLV-1前病毒易于在白血病细胞的转录起始位点附近整合（P =.006），并且在70%的情况下，前病毒的转录方向与整合的细胞基因的转录方向一致。更重要的是，在携带者细胞中的整合位点有利于α重复序列（11/56; 20%），而在白血病细胞中，他们不利于这些序列（2159; 3.4%）。总之，在从携带者到ATL发作的自然过程中，具有有利于病毒基因转录的整合位点的HTLV-I感染的细胞由于病毒基因表达增加而易于恶性转化。
Human T-cell leukemia virus type I (HTLV-1) is a causative agent of neoplastic disease, adult T-cell leukemia (ATL). Although the encoding viral proteins play an important role in oncogenesis, the role of the HTLV-1 proviral integration site remains unsolved. We determined the integration sites of HTLV-1 proviruses in ATL cells and HTLV-1-infected cells in asymptomatic carriers. In carrier and ATL cells, HTLV-1 provirus was integrated into the transcriptional unit at frequencies of 26.8% (15/56) and 33.9% (20/59), respectively, which were equivalent to the frequency calculated based on random integration (33.2%). In addition, HTLV-1 provirus was prone to integration near the transcriptional start sites in leukemic cells (P =.006), and the transcriptional direction of the provirus was in accordance with that of integrated cellular genes in 70% of cases. More importantly, the integration sites in the carrier cells favored the alphoid repetitive sequences (11/56; 20%) whereas in leukemic cells they disfavored these sequences (2159; 3.4%). Taken together, during natural course from carrier to onset of ATL, HTLV-I-infected cells with integration sites favorable for viral gene transcription are susceptible to malignant transformation due to increased viral gene expression.