RAG1 and RAG2 non-core regions are implicated in leukemogenesis and off-target V(D)J recombination in BCR-ABL1-driven...

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 Rag1 and Rag2 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 (Rag^f/f), core RAG1 (Rag1^c/c), and core RAG2 (Rag2^c/c). The Rag (Rag1 and Rag2) leukemia cells exhibited greater malignant tumor characteristics compared to Rag cells. Additionally, Rag cells showed higher frequency of off-target V(D)J recombination and oncogenic mutations than Rag. We also revealed decreased RAG cleavage accuracy in Rag cells and a smaller recombinant size in Rag1 cells, which could potentially exacerbate off-target V(D)J recombination in Rag 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.