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

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 mice thymic lymphomas. However, the genomic stability effects of non-core regions from both and in B-lymphoblastic leukemia ( 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 B-ALL in mice expressing full-length RAG (Rag), core RAG1 (Rag1), and core RAG2 (Rag2). The ( and ) leukemia cells exhibited greater malignant tumor characteristics compared to cells. Additionally, cells showed higher frequency of off-target V(D)J recombination and oncogenic mutations than . We also revealed decreased RAG cleavage accuracy in cells and a smaller recombinant size in cells, which could potentially exacerbate off-target V(D)J recombination in 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 B-ALL.