Hays E F, Bristol G C, McDougall S, Klotz J L, Kronenberg M
Department of Medicine, University of California, Los Angeles 90024.
Cancer Res. 1989 Aug 1;49(15):4225-30.
A chronological study of the individual thymic lobes of young AKR mice after neonatal inoculation of the oncogenic AKR retrovirus SL 3-3 was performed. 100% of mice treated in this manner develop lymphoma between 60 and 100 days of age. A search for early lymphoma cells in individual thymi was carried out by inoculating the thymocytes subcutaneously in syngeneic and intrathymically in syngeneic and semisyngeneic recipients. Tumor progression was observed in animals between 48 and 60 days of age. These animals have: (a) normal weight lobes, in which no lymphoma cells could be detected, (b) thymus-dependent lymphoma cells, in one or both normal weight lobes; (c) thymus-independent lymphoma cells, found in lobes of normal weight as well as in thymi enlarged by lymphoma cells. Thymocyte characteristics of virus-treated animals of 21 to 63 days of age were compared with those of age-matched controls. Beginning at 28 days a concordant, progressive with time, increase of thymocyte surface staining for the viral envelope glycoprotein gp70 was seen in all lobes from virus-treated animals. Evaluation of cell surface markers by two-color fluorescence with antibodies to CD4 and CD8 showed that after 50 days of age, thymic lobes with and without lymphomas had nonspecific, but marked, alterations of the typical thymocyte surface marker pattern. No characteristic CD4, CD8 surface phenotype was found in primary lymphomas. Using probes for the T-cell receptor J beta 2 gene segments and the Akv ecotropic virus gp70 envelope genes, oligoclonality in J beta 2 rearrangements and clonality using the Akv env genes was demonstrated in thymi with the thymus-dependent phenotype. In lymphomas T-cell receptor beta gene probes showed either oligoclonality or clonality. Clonal virus integrations were found in these lymphomas. These experiments suggest the following series of events in virus-accelerated AKR lymphomagenesis. First, lymphoma cells arise which are initially thymus-dependent and can appear in one or simultaneously in both thymic lobes. These progress to become thymus-independent, fully autonomous, tumor cells. Thymocytes close to or at the time of the initial transformation event show a marked disorder of differentiation defined by the alterations in the CD4, CD8 surface phenotype distribution.
对新生期接种致癌性AKR逆转录病毒SL 3-3的年轻AKR小鼠的各个胸腺叶进行了一项按时间顺序的研究。以这种方式处理的小鼠100%在60至100日龄之间发生淋巴瘤。通过将胸腺细胞皮下接种到同基因受体以及胸腺内接种到同基因和半同基因受体中，对各个胸腺中的早期淋巴瘤细胞进行了搜索。在48至60日龄的动物中观察到肿瘤进展。这些动物有：(a) 重量正常的叶，其中未检测到淋巴瘤细胞；(b) 胸腺依赖性淋巴瘤细胞，存在于一个或两个重量正常的叶中；(c) 胸腺非依赖性淋巴瘤细胞，在重量正常的叶以及被淋巴瘤细胞肿大的胸腺中均有发现。将21至63日龄经病毒处理的动物的胸腺细胞特征与年龄匹配的对照动物进行了比较。从28日龄开始，在经病毒处理的动物的所有叶中均观察到病毒包膜糖蛋白gp70的胸腺细胞表面染色随时间一致且逐渐增加。用抗CD4和CD8抗体进行双色荧光对细胞表面标志物进行评估表明，50日龄后，有淋巴瘤和无淋巴瘤的胸腺叶均出现典型胸腺细胞表面标志物模式的非特异性但明显的改变。在原发性淋巴瘤中未发现特征性的CD4、CD8表面表型。使用T细胞受体Jβ2基因片段和Akv嗜亲性病毒gp70包膜基因的探针，在具有胸腺依赖性表型的胸腺中证实了Jβ2重排中的寡克隆性以及使用Akv env基因的克隆性。在淋巴瘤中，T细胞受体β基因探针显示出寡克隆性或克隆性。在这些淋巴瘤中发现了克隆性病毒整合。这些实验提示了病毒加速的AKR淋巴瘤发生过程中的以下一系列事件。首先，出现最初为胸腺依赖性的淋巴瘤细胞，可出现在一个胸腺叶或同时出现在两个胸腺叶中。这些细胞进展为胸腺非依赖性、完全自主的肿瘤细胞。接近或在初始转化事件发生时的胸腺细胞显示出由CD4、CD8表面表型分布改变所定义的明显分化紊乱。
