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Off-Target V(D)J Recombination Drives Lymphomagenesis and Is Escalated by Loss of the Rag2 C Terminus.
Mijuskovic, Martina; Chou, Yi-Fan; Gigi, Vered; Lindsay, Cory R; Shestova, Olga; Lewis, Susanna M; Roth, David B.
Affiliation
  • Mijuskovic M; 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;
  • Chou YF; 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.
  • Gigi V; 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;
  • Lindsay CR; 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;
  • Shestova O; 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;
  • Lewis SM; 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.
  • Roth DB; 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.
Cell Rep ; 12(11): 1842-52, 2015 Sep 22.
Article in En | MEDLINE | ID: mdl-26365182
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Thymus Neoplasms / Tumor Suppressor Proteins / DNA-Binding Proteins / V(D)J Recombination / Lymphoma Type of study: Prognostic_studies Limits: Animals Language: En Journal: Cell Rep Year: 2015 Document type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Thymus Neoplasms / Tumor Suppressor Proteins / DNA-Binding Proteins / V(D)J Recombination / Lymphoma Type of study: Prognostic_studies Limits: Animals Language: En Journal: Cell Rep Year: 2015 Document type: Article