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

Abstract

AbstractThe 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 cRAG1 and cRAG2 inBCR-ABL1+B-lymphoblastic leukemia (BCR-ABL1+B-ALL), the characteristics, and mechanisms of non-core regions in suppressing off-target V(D)J recombination remains unclear. Here, we established three mice models ofBCR-ABL1+B-ALL infull-length RAG(fRAG),core RAG1(cRAG1), andcore RAG2(cRAG2) mice. ThecRAG(cRAG1 and cRAG2) leukemia cells exhibited greatr malignant tumor characteristics compared tofRAGcells. Additionally,cRAGcells showed higher frequency of off-target V(D)J recombination and oncogenic mutations thanfRAG. We also revealed decreased RAG binding accuracy incRAGcells and a smaller recombinant size incRAG1cells, which could potentially exacerbate off-target V(D)J recombination incRAGcells. 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 inBCR-ABL1+B-ALL.