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

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