RAG1 and RAG2 non-core regions are implicated in leukemogenesis and off-target VJ 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 Tp53.sup.-/- mice thymic l...

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Published in:eLife 2024, Vol.12
Main Authors: Yu, Xiaozhuo, Zhou, Wen, Chen, Xiaodong, He, Shunyu, Qin, Mengting, Yuan, Meng, Wang, Yang, Odhiambo, Woodvine Otieno, Miao, Yinsha, Ji, Yanhong
Format: Report
Language:English
Subjects:
Development and progression
Gene expression
Gene mutations
Genetic aspects
Genetic recombination
Leukemia research
Lymphocytic leukemia
Online Access:Get full text
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Summary: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.sup.-/- mice thymic lymphomas. However, the genomic stability effects of non-core regions from both Rag1.sup.c/c and Rag2.sup.c/c in BCR-ABL1.sup.+ B-lymphoblastic leukemia (BCR-ABL1.sup.+ 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.sup.+ B-ALL in mice expressing full-length RAG (Rag.sup.f/f), core RAG1 (Rag1.sup.c/c), and core RAG2 (Rag2.sup.c/c). The Rag.sup.c/c (Rag1.sup.c/c and Rag2.sup.c/c) leukemia cells exhibited greater malignant tumor characteristics compared to Rag.sup.f/f cells. Additionally, Rag.sup.c/c cells showed higher frequency of off-target V(D)J recombination and oncogenic mutations than Rag.sup.f/f. We also revealed decreased RAG cleavage accuracy in Rag.sup.c/c cells and a smaller recombinant size in Rag1.sup.c/c cells, which could potentially exacerbate off-target V(D)J recombination in Rag.sup.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.sup.+ B-ALL.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.91030