PDF(Pubmed)
Abstract：
The evolutionary conservation of non-core RAG regions suggests significant roles that might involve quantitative or qualitative alterations in RAG activity. Off-target V(D)J recombination contributes to lymphomagenesis and is exacerbated by RAG2\' C-terminus absence in Tp53-/- mice thymic lymphomas. However, the genomic stability effects of non-core regions from both Rag1c/c and Rag2c/c in BCR-ABL1+ B-lymphoblastic leukemia (BCR-ABL1+ B-ALL), the characteristics, and mechanisms of non-core regions in suppressing off-target V(D)J recombination remain unclear. Here, we established three mouse models of BCR-ABL1+ B-ALL in mice expressing full-length RAG (Ragf/f), core RAG1 (Rag1c/c), and core RAG2 (Rag2c/c). The Ragc/c (Rag1c/c and Rag2c/c) leukemia cells exhibited greater malignant tumor characteristics compared to Ragf/f cells. Additionally, Ragc/c cells showed higher frequency of off-target V(D)J recombination and oncogenic mutations than Ragf/f. We also revealed decreased RAG cleavage accuracy in Ragc/c cells and a smaller recombinant size in Rag1c/c cells, which could potentially exacerbate off-target V(D)J recombination in Ragc/c cells. In conclusion, these findings indicate that the non-core RAG regions, particularly the non-core region of RAG1, play a significant role in preserving V(D)J recombination precision and genomic stability in BCR-ABL1+ B-ALL.
摘要：
非核心RAG区域的进化保守性表明可能涉及RAG活性的定量或定性改变的重要作用。在Tp53-/-小鼠胸腺淋巴瘤中，脱靶V（D）J重组有助于淋巴形成，并因RAG2\'C末端缺失而加剧。然而,来自Rag1c/c和Rag2c/c的非核心区域在BCR-ABL1+B淋巴细胞白血病（BCR-ABL1+B-ALL）中的基因组稳定性效应，的特点,非核心区域抑制脱靶V（D）J重组的机制尚不清楚。这里,我们在表达全长RAG（Ragf/f）的小鼠中建立了三种BCR-ABL1B-ALL的小鼠模型，核心RAG1（Rag1c/c），和核心RAG2（Rag2c/c）。与Ragf/f细胞相比，Ragc/c（Rag1c/c和Rag2c/c）白血病细胞表现出更大的恶性肿瘤特征。此外,Ragc/c细胞显示出比Ragf/f更高的脱靶V（D）J重组和致癌突变的频率。我们还发现Ragc/c细胞中RAG裂解的准确性下降，Rag1c/c细胞中重组体的大小较小，这可能会加剧Ragc/c细胞中的脱靶V（D）J重组。总之,这些结果表明，非核心RAG区域，特别是RAG1的非核心区域，在BCR-ABL1B-ALL中保持V（D）J重组精度和基因组稳定性中起重要作用。
