title: RAG-mediated V(D)J recombination is not essential for tumorigenesis in Atm-deficient mice.
abstract: Atm-deficient mice die of malignant thymic lymphomas characterized by translocations within the Tcr alpha/delta 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 alpha/delta 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 alpha/delta 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.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, Howard Hughes Medical Institute-NIH Research Scholars Program, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Petiniot
authors.forename: Zoë
authors.initials: Z
authors.lastname: Weaver
authors.forename: Melanie
authors.initials: M
authors.lastname: Vacchio
authors.forename: Rhuna
authors.initials: R
authors.lastname: Shen
authors.forename: Danny
authors.initials: D
authors.lastname: Wangsa
authors.forename: Carrolee
authors.initials: C
authors.lastname: Barlow
authors.forename: Michael
authors.initials: M
authors.lastname: Eckhaus
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Anthony
authors.initials: A
authors.lastname: Wynshaw-Boris
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Hodes
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics*; D016654:Genes, RAG-1 / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D017404:In Situ Hybridization, Fluorescence; D008223:Lymphoma / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics*; D016019:Survival Analysis; D013953:Thymus Neoplasms / Q000235:genetics*; D013997:Time Factors; D014178:Translocation, Genetic / Q000235:genetics; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C499308:Rag2 protein, mouse; D025521:Tumor Suppressor Proteins; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases