title: Off-Target V(D)J Recombination Drives Lymphomagenesis and Is Escalated by Loss of the Rag2 C Terminus.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Abramson Family Cancer Research Institute, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Department of Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.
authors.forename: Martina
authors.initials: M
authors.lastname: Mijušković
authors.affiliation: Department of Pathology and Laboratory Medicine, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Abramson Family Cancer Research Institute, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Chou
authors.affiliation: Department of Pathology and Laboratory Medicine, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Abramson Family Cancer Research Institute, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; The Boston Consulting Group, 1735 Market Street, Philadelphia, PA 19103, USA.
authors.forename: Vered
authors.initials: V
authors.lastname: Gigi
authors.affiliation: Department of Pathology and Laboratory Medicine, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Abramson Family Cancer Research Institute, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Cardeza Foundation for Hematological Research, Thomas Jefferson University, 394 Jefferson Alumni Hall, 1020 Locust Street, Philadelphia, PA 19104, USA.
authors.forename: Cory R
authors.initials: CR
authors.lastname: Lindsay
authors.affiliation: Department of Pathology and Laboratory Medicine, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Abramson Family Cancer Research Institute, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Translational Research Program, Abramson Family Research Cancer Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Shestova
authors.affiliation: Department of Pathology and Laboratory Medicine, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Abramson Family Cancer Research Institute, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. Electronic address: susle@mail.med.upenn.edu.
authors.forename: Susanna M
authors.initials: SM
authors.lastname: Lewis
authors.affiliation: Department of Pathology and Laboratory Medicine, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Abramson Family Cancer Research Institute, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. Electronic address: david.roth2@uphs.upenn.edu.
authors.forename: David B
authors.initials: DB
authors.lastname: Roth
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D013953:Thymus Neoplasms / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D060152:V(D)J Recombination
chemical_list: D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D025521:Tumor Suppressor Proteins