Recombinase-activating gene (RAG) 2-mediated V(D)J recombination is not essential for tumorigenesis in Atm-deficient mice.
Recombinase-activating gene (RAG) 2-mediated V(D)J recombination is not essential for tumorigenesis in Atm-deficient mice.
复制标题
重组酶激活基因 (RAG) 2 介导的 V(D)J 重组对于 Atm 缺陷小鼠的肿瘤发生并不是必需的。
DOI：
10.1073/pnas.97.12.6664
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发表时间：
2000
影响因子：
11.1
通讯作者：
Hodes,RJ
中科院分区：
文献类型：
--
作者：
Petiniot,LK;Weaver,Z;Barlow,C;Shen,R;Eckhaus,M;Steinberg,SM;Ried,T;Wynshaw-Boris,A;Hodes,RJ
大多数Atm缺陷小鼠在4-5月龄死于恶性胸腺淋巴瘤。这些肿瘤的细胞遗传学异常在Tcr α/δ基因座内一致地被确定，表明肿瘤发生继发于对V（D）J重组期间发生的双链DNA断裂的异常反应。由于V（D）J重组是一个依赖于重组酶激活基因（RAG）的过程，我们产生了Rag 2 −/−Atm−/−小鼠来评估胸腺淋巴瘤发生中RAG依赖性重组的需要。与预期相反，这里提供的数据表明，Atm −/−小鼠恶性胸腺淋巴瘤的发生不能通过RAG-2的缺失来阻止，因此不依赖于V（D）J重组。与Atm −/−小鼠相比，Rag 2 −/−Atm−/−小鼠的恶性胸腺淋巴瘤发生频率较低，潜伏期较长。重要的是，这些肿瘤的细胞遗传学分析表明，在每个肿瘤中发生多个染色体异常，但这些都不涉及Tcr α/δ位点。来自TCR转基因Rag 2 −/−Atm−/−小鼠的非恶性外周T细胞也显示易位频率大幅增加，表明这些易位是肿瘤发生过程中的早期事件。这些数据与Atm −/−小鼠肿瘤发生的主要机制是通过染色体易位和继发于双链DNA断裂异常反应的其他异常的假设一致。此外，这些数据表明，V（D）J重组是一个关键的，但不是必需的，在此期间，Atm缺陷的胸腺细胞容易发展染色体畸变，使其易于恶性转化。
The majority ofAtm-deficient mice die of malignant thymic lymphoma by 4–5 mo of age. Cytogenetic abnormalities in these tumors are consistently identified within theTcr α/δlocus, suggesting that tumorigenesis is secondary to aberrant responses to double-stranded DNA breaks that occur during V(D)J recombination. Since V(D)J recombination is a recombinase-activating gene (RAG)-dependent process, we generatedRag2−/−Atm−/−mice to assess the requirement for RAG-dependent recombination in thymic lymphomagenesis. In contrast to expectation, the data presented here indicate that development of malignant thymic lymphoma inAtm−/−mice is not prevented by loss of RAG-2 and thus is not dependent on V(D)J recombination. Malignant thymic lymphomas inRag2−/−Atm−/−mice occurred at a lower frequency and with a longer latency as compared withAtm−/−mice. Importantly, cytogenetic analysis of these tumors indicated that multiple chromosomal abnormalities occurred in each tumor, but that none of these involved theTcr α/δlocus. Nonmalignant peripheral T cells from TCR-transgenicRag2−/−Atm−/−mice also revealed a substantial increase in translocation frequency, suggesting that these translocations are early events in the process of tumorigenesis. These data are consistent with the hypothesis that the major mechanism of tumorigenesis inAtm−/−mice is via chromosomal translocations and other abnormalities that are secondary to aberrant responses to double-stranded DNA breaks. Furthermore, these data suggest that V(D)J recombination is a critical, but not essential, event during whichAtm-deficient thymocytes are susceptible to developing chromosome aberrations that predispose to malignant transformation.