Mercer J A, Jenkins N A, Copeland N G
Mammalian Genetics Laboratory, National Cancer Institute Frederick Cancer Research Facility, Maryland 21701.
J Virol. 1990 Oct;64(10):5199-203. doi: 10.1128/JVI.64.10.5199-5203.1990.
DBA/2 mice carry a single endogenous ecotropic murine leukemia provirus, Emv-3, that is replication defective because of a single nucleotide substitution in codon 3 of p15gag. However, when weanling DBA/2 mice are treated percutaneously with 7,12-dimethylbenz(a)anthracene (DMBA), ecotropic virus replication is induced in almost all of the treated mice. Previous studies have shown that this induction results from DMBA-induced reverse mutations in codon 3 that allow efficient virus replication. In addition to ecotropic virus replication, DMBA also induces lymphomas in 100% of the treated mice. These results have raised the possibility that ecotropic virus replication is causally associated with the development of lymphomas in DBA/2 mice, perhaps via the insertional activation or mutation of cellular proto-oncogenes. To test this possibility, we compared lymphoma incidence after percutaneous DMBA treatment in DBA/2J-dv/dv mice, which carry two copies of Emv-3, with lymphoma incidence in DBA/2J-d+18J/d+18J mice, which lost both copies of Emv-3 by homologous recombination involving the long terminal repeat sequences. The results of this study conclusively demonstrated that Emv-3 is not causally associated with the development of DMBA-induced lymphomas in DBA/2J mice. Interestingly, histopathological and molecular analyses of the lymphomas indicated that the majority of the lymphomas in both strains of mice were of the B-cell lineage. This was unanticipated, since the majority of chemically induced lymphomas in other inbred strains are thymic lymphomas, presumably of the T-cell lineage. Thus, DBA/2 mice appear to present a unique model system for the investigation of chemically induced B-cell lymphomas in mice.
DBA/2小鼠携带一种单一的内源性嗜亲性鼠白血病前病毒Emv-3，由于p15gag第3密码子中的单个核苷酸替换，该病毒复制存在缺陷。然而，当用7,12-二甲基苯并(a)蒽（DMBA）对断奶的DBA/2小鼠进行经皮处理时，几乎所有处理过的小鼠中都会诱导嗜亲性病毒复制。先前的研究表明，这种诱导是由DMBA诱导的第3密码子中的反向突变导致的，从而使病毒能够有效复制。除了嗜亲性病毒复制外，DMBA还会在100%的处理过的小鼠中诱导淋巴瘤。这些结果增加了一种可能性，即嗜亲性病毒复制与DBA/2小鼠淋巴瘤的发生存在因果关系，可能是通过细胞原癌基因的插入激活或突变。为了验证这种可能性，我们比较了携带两份Emv-3的DBA/2J-dv/dv小鼠经皮DMBA处理后的淋巴瘤发生率与通过涉及长末端重复序列的同源重组丢失两份Emv-3的DBA/2J-d+18J/d+18J小鼠的淋巴瘤发生率。这项研究的结果确凿地证明，Emv-3与DBA/2J小鼠中DMBA诱导的淋巴瘤的发生没有因果关系。有趣的是，对淋巴瘤的组织病理学和分子分析表明，两种品系小鼠中的大多数淋巴瘤都是B细胞谱系的。这是出乎意料的，因为在其他近交系中，大多数化学诱导的淋巴瘤是胸腺淋巴瘤，大概是T细胞谱系的。因此，DBA/2小鼠似乎为研究小鼠化学诱导的B细胞淋巴瘤提供了一个独特的模型系统。
