Synergy between a human c-myc transgene and p53 null genotype in murine thymic lymphomas: contrasting effects of homozygous and heterozygous p53 loss.
Synergy between a human c-myc transgene and p53 null genotype in murine thymic lymphomas: contrasting effects of homozygous and heterozygous p53 loss.
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人 c-myc 转基因和 p53 无效基因型在小鼠胸腺淋巴瘤中的协同作用：纯合子和杂合子 p53 缺失的对比效应。
作者：
K. Blyth;A. Terry;M. O’Hara;E. Baxter;M. Campbell;M. Stewart;L. Donehower;D. Onions;J. Neil;E. Cameron
c-myc癌基因的激活和p53肿瘤抑制基因的功能丧失是肿瘤形成中最常见的遗传病变，但它们的联合作用以前没有被研究过。通过将人c-myc（CD 2-myc）转基因小鼠和携带无活性p53等位基因（p53-/-）的小鼠一起繁殖，我们发现这些遗传病变在体内协同作用。携带CD 2-myc转基因和纯合子p53无效突变（p53-/-/CD 2-myc）的后代是可行的，但与两个亲本组相比，胸腺淋巴瘤的发生频率显着增加，潜伏期减少。肿瘤表型与先前记录的CD 2-myc小鼠（主要为CD 3+、CD 4 +8+）相似，但p53-/-/CD 2-myc小鼠的肿瘤克隆复杂性和转移显著更大。相比之下，在6个月的观察期内，在p53+/-/CD 2-myc与p53+/+/CD 2-myc小鼠中未观察到肿瘤发生率显著增加。然而，在p53+/-/CD 2-myc淋巴瘤中，野生型p53在一定比例的肿瘤细胞中的丢失表明，野生型等位基因的丢失可能发生在这些肿瘤的晚期进展步骤，而不是起始步骤。我们认为，p53功能丧失可能与CD 2-myc转基因在胸腺淋巴瘤发展的一个以上的阶段。
Activation of the c-myc oncogene and functional loss of the p53 tumour suppressor gene are among the most frequently recorded genetic lesions in neoplasia but their combined effect has not previously been investigated. By breeding together mice transgenic for human c-myc (CD2-myc) and mice carrying an inactive p53 allele (p53-/-) we found that these genetic lesions act synergistically in vivo. Offspring carrying the CD2-myc transgene and the homozygous p53 null mutation (p53-/-/CD2-myc) were viable but developed thymic lymphomas with dramatically increased frequency and reduced latency compared to both parental groups. The tumour phenotype was similar to that previously recorded for CD2-myc mice (predominantly CD3+, CD4+8+) but tumour clonal complexity and metastasis was significantly greater in the p53-/-/CD2-myc mice. In contrast, no significant increase in tumour incidence was seen in p53+/-/CD2-myc vs p53+/+/CD2-myc mice over a 6 month observation period. However, the loss of wild type p53 in a proportion of tumour cells in p53+/-/CD2-myc lymphomas suggests that wild type allele loss can occur as a late progression step rather than an initiating step in these tumours. We suggest that p53 loss of function may collaborate with the CD2-myc transgene at more than one stage in thymic lymphoma development.