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。