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Molecular and Cellular Biology, May 2002, p. 3174-3177, Vol. 22, No. 9
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.9.3174-3177.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

RAG-Mediated V(D)J Recombination Is Not Essential for Tumorigenesis in Atm-Deficient Mice

Lisa K. Petiniot,^1,2 Zoë Weaver,^3, Melanie Vacchio,¹ Rhuna Shen,^1,2 Danny Wangsa,³ Carrolee Barlow,^4, Michael Eckhaus,⁵ Seth M. Steinberg,⁶ Anthony Wynshaw-Boris,^4,7 Thomas Ried,³ and Richard J. Hodes^1,8*

Experimental Immunology Branch,¹ Genetics Branch,³ Biostatistics and Data Management Section, Office of the Director, National Cancer Institute,⁶ Howard Hughes Medical Institute-NIH Research Scholars Program,² Genetic Disease Research Branch, National Human Genome Research Institute,⁴ Veterinary Resources Program, Office of Research Services,⁵ National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892,⁸ San Diego School of Medicine, University of California, La Jolla, California 92093⁷

Received 4 October 2001/ Returned for modification 24 January 2002/ Accepted 4 February 2002

Atm-deficient mice die of malignant thymic lymphomas characterized by translocations within the Tcr/ locus, suggesting that tumorigenesis is secondary to aberrant responses to double-stranded DNA (dsDNA) breaks that occur during RAG-dependent V(D)J recombination. We recently demonstrated that development of thymic lymphoma in Atm^-/- mice was not prevented by loss of RAG-2. Thymic lymphomas that developed in Rag2^-/- Atm^-/- mice contained multiple chromosomal abnormalities, but none of these involved the Tcr/ locus. These findings indicated that tumorigenesis in Atm^-/- mice is mediated by chromosomal translocations secondary to aberrant responses to dsDNA breaks and that V(D)J recombination is an important, but not essential, event in susceptibility. In contrast to these findings, it was recently reported that Rag1^-/- Atm^-/- mice do not develop thymic lymphomas, a finding that was interpreted as demonstrating a requirement for RAG-dependent recombination in the susceptibility to tumors in Atm-deficient mice. To test the possibility that RAG-1 and RAG-2 differ in their roles in tumorigenesis, we studied Rag1^-/- Atm^-/- mice in parallel to our previous Rag2^-/- Atm^-/- study. We found that thymic lymphomas occur at high frequency in Rag1^-/- Atm^-/- mice and resemble those that occur in Rag2^-/- Atm^-/- mice. These results indicate that both RAG-1 and RAG-2 are necessary for tumorigenesis involving translocation in the Tcr/ locus but that Atm deficiency leads to tumors through a broader RAG-independent predisposition to translocation, related to a generalized defect in dsDNA break repair.

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* Corresponding author. Mailing address: National Institutes of Health, Building 31, Room 5C35, Bethesda, MD 20892. Phone: (301) 496-3129. Fax: (301) 496-0887. E-mail: richard_hodes{at}nih.gov.

Present address: Avalon Pharmaceuticals, Gaithersburg, Md.

Present address: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037.

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Molecular and Cellular Biology, May 2002, p. 3174-3177, Vol. 22, No. 9
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.9.3174-3177.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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