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

Lisa K. Petiniot; Zoe Weaver; Melanie VacchioRhuna ShenDanny WangsaCarrolee BarlowMichael EckhausSeth M. SteinbergAnthony Wynshaw-BorisThomas Ried

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

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Atm-deficient mice die of malignant thymic lymphomas characterized by translocations within the Tcrα/δ 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 Tcrα/δ 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 Tcrα/δ 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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《Molecular and Cellular Biology》 |2002年第9期|3174-3177|共4页
作者
Lisa K. Petiniot; Zoe Weaver; Melanie VacchioRhuna ShenDanny WangsaCarrolee BarlowMichael EckhausSeth M. SteinbergAnthony Wynshaw-BorisThomas Ried;
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Experimental Immunology Branch, National Institutes of Health, Bethesda, Maryland 20892;

Avalon Pharmaceuticals, Gaithersburg, Md.;

Genetics Branch, National Institutes of Health, Bethesda, Maryland 20892Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037Veterinary Resources Program, Office of Research Services, National Institutes of Health, Bethesda, Maryland 20892Biostatistics and Data Management Section, Office of the Director, National Institutes of Health, Bethesda, Maryland 20892Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892;

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

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