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

Authors

• Martina Mijušković, Department of Pathology and Laboratory Medicine, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania; Abramson Family Cancer Research Institute, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania; Department of Genetics and Epidemiology, The Institute of Cancer Research
• Yi-Fan Chou, Department of Pathology and Laboratory Medicine, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania; Abramson Family Cancer Research Institute, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania
• Vered Gigi, Department of Pathology and Laboratory Medicine, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania; Abramson Family Cancer Research Institute, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania; The Boston Consulting Group
• Cory R Lindsay, Department of Pathology and Laboratory Medicine, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania; Abramson Family Cancer Research Institute, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania; Cardeza Foundation for Hematological Research, Thomas Jefferson University
• Olga Shestova, Department of Pathology and Laboratory Medicine, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania; Abramson Family Cancer Research Institute, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania; Translational Research Program, Abramson Family Research Cancer Institute, University of Pennsylvania
• Susanna M Lewis, Department of Pathology and Laboratory Medicine, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania; Abramson Family Cancer Research Institute, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania
• David B Roth, Department of Pathology and Laboratory Medicine, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania; Abramson Family Cancer Research Institute, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania

Document Type

Article

Publication Date

9-22-2015

Comments

This article has been peer reviewed. It was published in: Cell Reports.

Volume 12, Issue 11, 22 September 2015, Pages 1842-1852.

The published version is available at DOI: 10.1016/j.celrep.2015.08.034

Copyright © 2015 The Authors.

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.

Recommended Citation

Mijušković, Martina; Chou, Yi-Fan; Gigi, Vered; Lindsay, Cory R; Shestova, Olga; Lewis, Susanna M; and Roth, David B, "Off-Target V(D)J Recombination Drives Lymphomagenesis and Is Escalated by Loss of the Rag2 C Terminus." (2015). Cardeza Foundation for Hematologic Research. Paper 27.
https://jdc.jefferson.edu/cardeza_foundation/27