Off-Target V(D)J Recombination Drives Lymphomagenesis and Is Escalated by Loss of the Rag2 C Terminus

• Published in: Cell reports (Cambridge) 2015-09, Vol.12 (11), p.1842-1852
• Main Authors: Mijušković, Martina, Chou, Yi-Fan, Gigi, Vered, Lindsay, Cory R., Shestova, Olga, Lewis, Susanna M., Roth, David B.
• Format: Article
• Language: English
• Subjects: Animals; Disease Models, Animal; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Lymphoma - genetics; Lymphoma - metabolism; Mice; Mice, Inbred C57BL; Thymus Neoplasms - genetics; Thymus Neoplasms - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; V(D)J Recombination
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2015.08.034

Genome-wide analysis of thymic lymphomas from Tp53−/− mice with wild-type or C-terminally truncated Rag2 revealed numerous off-target, RAG-mediated DNA rearrangements. A significantly higher fraction of these errors mutated known and suspected oncogenes/tumor suppressor genes than did sporadic rearrangements (p < 0.0001). This tractable mouse model recapitulates recent findings in human pre-B ALL and allows comparison of wild-type and mutant RAG2. Recurrent, RAG-mediated deletions affected Notch1, Pten, Ikzf1, Jak1, Phlda1, Trat1, and Agpat9. Rag2 truncation substantially increased the frequency of off-target V(D)J recombination. The data suggest that interactions between Rag2 and a specific chromatin modification, H3K4me3, support V(D)J recombination fidelity. Oncogenic effects of off-target rearrangements created by this highly regulated recombinase may need to be considered in design of site-specific nucleases engineered for genome modification. [Display omitted] •V(D)J recombination errors are investigated in lymphomas from p53-deficient mice•Numerous off-target rearrangements are found scattered across tumor genomes•These rearrangements target known and suspected oncogenes and tumor suppressors•Loss of Rag2 C terminus increases the frequency of off-target V(D)J recombination To investigate the role of V(D)J recombination errors in oncogenesis, Mijuskovic et al. analyzed whole genomes of lymphomas spontaneously arising in p53-deficient mice. The systematic analysis revealed numerous off-target, RAG-mediated rearrangements in known and suspected cancer genes, which were escalated by the loss of Rag2 C terminus.