HTLV-I viral escape and host genetic changes in the development of adult T cell leukemia
HTLV-I viral escape and host genetic changes in the development of adult T cell leukemia
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DOI：
10.1002/ijc.21328
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发表时间：
2006-01-15
影响因子：
6.4
通讯作者：
Osame, M
中科院分区：
文献类型：
--
作者：
Furukawa, Y;Tara, M;Osame, M
在成人T细胞白血病（ATL）的发病机制中，人T细胞嗜淋巴细胞病毒I型（HTLV-I）Tax蛋白的致癌作用、病毒从宿主免疫系统逃逸以及宿主遗传变化已被认为是促成因素。我们检测了tax基因中的提前终止密码子作为HTLV-I携带者中可能导致HTLV-I逃避细胞毒性T淋巴细胞（CTL）应答的突变之一，以测试在ATL发展的早期阶段是否可能出现假定的CTL逃避突变体以及具有这种突变的HTLV-I感染细胞是否可以随后增殖。我们还研究了细胞周期蛋白依赖性激酶抑制剂4（INK 4）基因的缺失和p53基因的突变与HTLV-I基因组中的变化相结合，在急性型ATL测试宿主的遗传变化是否促进携带假定的CTL逃逸突变的ATL细胞的恶性转化。tax基因的提前终止密码子存在于少数非ATL HTLV-Ⅰ携带者中，但不存在于个体最常见的HTLV-Ⅰ序列中。这一具有提前终止密码子的少数群体随后在3名无症状携带者中没有扩增。HTLV-I基因突变或缺失者中也有INK 4基因缺失或p53基因突变者。我们的研究结果表明，CTL逃逸突变可以发生在ATL发展的早期阶段，某些宿主的遗传变化有利于ATL的侵略性形式的发展。(c)2005年威利-利斯。Inc.
In the pathogenesis of adult T cell leukemia (ATL), an oncogenetic role of the human T cell lymphotropic virus type I (HTLV-I) Tax protein, viral escape from the host immune system, and host genetic changes have been proposed as contributory factors. We examined the premature stop codons in tax gene as one of the mutations that may lead to escape of HTLV-I from the cytotoxic T lymphocyte (CTL) response in HTLV-I carriers, to test whether a putative CTL escape mutant can emerge in the early stage of ATL development and whether HTLV-I infected cells with such a mutation can proliferate subsequently. We also examined deletion of cyclin-dependent kinase inhibitor 4 (INK4) genes and mutation of p53 gene in combination with changes in the HTLV-I genome in acute type ATL to test whether host genetic changes promoted the malignant transformation of ATL cells that carry putative CTL escape mutations. The premature stop codon in tax gene existed in many non-ATL HTLV-I carriers as a minor population but not in the commonest HTLV-I sequence of the individual. This minor population with a premature stop codon did not expand subsequently in 3 asymptomatic carriers tested. There were cases who had a mutation or deletion in HTLV-I who also have either deletion of INK4 genes or mutation in p53 gene. Our findings suggest that CTL escape mutation can occur at an early stage of ATL development, and that certain host genetic changes favor the development of the aggressive form of ATL. (c) 2005 Wiley-Liss. Inc.