Petiniot Lisa K, Weaver Zoë, Vacchio Melanie, Shen Rhuna, Wangsa Danny, Barlow Carrolee, Eckhaus Michael, Steinberg Seth M, Wynshaw-Boris Anthony, Ried Thomas, Hodes Richard J
Experimental Immunology Branch, National Cancer Institute, Howard Hughes Medical Institute-NIH Research Scholars Program, National Institutes of Health, Bethesda, Maryland 20892, USA.
Mol Cell Biol. 2002 May;22(9):3174-7. doi: 10.1128/MCB.22.9.3174-3177.2002.
Atm-deficient mice die of malignant thymic lymphomas characterized by translocations within the Tcr alpha/delta locus, suggesting that tumorigenesis is secondary to aberrant responses to double-stranded DNA (dsDNA) breaks that occur during RAG-dependent V(D)J recombination. We recently demonstrated that development of thymic lymphoma in Atm(-/-) mice was not prevented by loss of RAG-2. Thymic lymphomas that developed in Rag2(-/-) Atm(-/-) mice contained multiple chromosomal abnormalities, but none of these involved the Tcr alpha/delta locus. These findings indicated that tumorigenesis in Atm(-/-) mice is mediated by chromosomal translocations secondary to aberrant responses to dsDNA breaks and that V(D)J recombination is an important, but not essential, event in susceptibility. In contrast to these findings, it was recently reported that Rag1(-/-) Atm(-/-) mice do not develop thymic lymphomas, a finding that was interpreted as demonstrating a requirement for RAG-dependent recombination in the susceptibility to tumors in Atm-deficient mice. To test the possibility that RAG-1 and RAG-2 differ in their roles in tumorigenesis, we studied Rag1(-/-) Atm(-/-) mice in parallel to our previous Rag2(-/-) Atm(-/-) study. We found that thymic lymphomas occur at high frequency in Rag1(-/-) Atm(-/-) mice and resemble those that occur in Rag2(-/-) Atm(-/-) mice. These results indicate that both RAG-1 and RAG-2 are necessary for tumorigenesis involving translocation in the Tcr alpha/delta locus but that Atm deficiency leads to tumors through a broader RAG-independent predisposition to translocation, related to a generalized defect in dsDNA break repair.
Atm基因缺陷的小鼠死于恶性胸腺淋巴瘤，其特征是Tcrα/δ基因座内发生易位，这表明肿瘤发生是对RAG依赖性V(D)J重组过程中出现的双链DNA（dsDNA）断裂异常反应的继发结果。我们最近证明，RAG-2缺失并不能预防Atm(-/-)小鼠胸腺淋巴瘤的发生。在Rag2(-/-)Atm(-/-)小鼠中发生的胸腺淋巴瘤含有多种染色体异常，但这些异常均未涉及Tcrα/δ基因座。这些发现表明，Atm(-/-)小鼠的肿瘤发生是由对dsDNA断裂异常反应继发的染色体易位介导的，并且V(D)J重组是易感性中的一个重要但非必需事件。与这些发现相反，最近有报道称Rag1(-/-)Atm(-/-)小鼠不会发生胸腺淋巴瘤，这一发现被解释为表明在Atm基因缺陷小鼠对肿瘤的易感性中需要RAG依赖性重组。为了测试RAG-1和RAG-2在肿瘤发生中的作用是否不同，我们与之前对Rag-2(-/-)Atm(-/-)小鼠的研究平行，对Rag1(-/-)Atm(-/-)小鼠进行了研究。我们发现Rag1(-/-)Atm(-/-)小鼠中胸腺淋巴瘤的发生率很高，并且与Rag2(-/-)Atm(-/-)小鼠中发生的淋巴瘤相似。这些结果表明，RAG-1和RAG-2对于涉及Tcrα/δ基因座易位的肿瘤发生都是必需的，但Atm基因缺陷通过更广泛的与dsDNA断裂修复普遍缺陷相关的RAG非依赖性易位倾向导致肿瘤。
