{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:17:51Z","timestamp":1791274671976,"version":"4.1.0"},"reference-count":23,"publisher":"National Academy of Sciences","issue":"12","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2000,6,6]]},"abstract":"<jats:p>\n                    The majority of\n                    <jats:italic>Atm<\/jats:italic>\n                    -deficient mice die of malignant thymic lymphoma by 4\u20135 mo of age. Cytogenetic abnormalities in these tumors are consistently identified within the\n                    <jats:italic>Tcr \u03b1\/\u03b4<\/jats:italic>\n                    locus, suggesting that tumorigenesis is secondary to aberrant responses to double-stranded DNA breaks that occur during V(D)J recombination. Since V(D)J recombination is a recombinase-activating gene (RAG)-dependent process, we generated\n                    <jats:italic>Rag2<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <jats:italic>Atm<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice to assess the requirement for RAG-dependent recombination in thymic lymphomagenesis. In contrast to expectation, the data presented here indicate that development of malignant thymic lymphoma in\n                    <jats:italic>Atm<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice is not prevented by loss of RAG-2 and thus is not dependent on V(D)J recombination. Malignant thymic lymphomas in\n                    <jats:italic>Rag2<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <jats:italic>Atm<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice occurred at a lower frequency and with a longer latency as compared with\n                    <jats:italic>Atm<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice. Importantly, cytogenetic analysis of these tumors indicated that multiple chromosomal abnormalities occurred in each tumor, but that none of these involved the\n                    <jats:italic>Tcr \u03b1\/\u03b4<\/jats:italic>\n                    locus. Nonmalignant peripheral T cells from TCR-transgenic\n                    <jats:italic>Rag2<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <jats:italic>Atm<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice also revealed a substantial increase in translocation frequency, suggesting that these translocations are early events in the process of tumorigenesis. These data are consistent with the hypothesis that the major mechanism of tumorigenesis in\n                    <jats:italic>Atm<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice is via chromosomal translocations and other abnormalities that are secondary to aberrant responses to double-stranded DNA breaks. Furthermore, these data suggest that V(D)J recombination is a critical, but not essential, event during which\n                    <jats:italic>Atm<\/jats:italic>\n                    -deficient thymocytes are susceptible to developing chromosome aberrations that predispose to malignant transformation.\n                  <\/jats:p>","DOI":"10.1073\/pnas.97.12.6664","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:38:21Z","timestamp":1027679901000},"page":"6664-6669","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":64,"title":["Recombinase-activating gene (RAG) 2-mediated V(D)J recombination is not essential for tumorigenesis in\n                    <i>Atm<\/i>\n                    -deficient mice"],"prefix":"10.1073","volume":"97","author":[{"given":"Lisa K.","family":"Petiniot","sequence":"first","affiliation":[{"name":"Experimental Immunology Branch, Genetics Department, and Biostatistics and Data Management Section, Office of the Director of the Division of Clinical Sciences, National Cancer Institute; Genetic Disease Research Branch, National Human Genome Research Institute; Veterinary Resources Program, Office of Research Services; National Institute on Aging, National Institutes of Health, Bethesda, MD 20892; and Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, One..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zo\u00eb","family":"Weaver","sequence":"additional","affiliation":[{"name":"Experimental Immunology Branch, Genetics Department, and Biostatistics and Data Management Section, Office of the Director of the Division of Clinical Sciences, National Cancer Institute; Genetic Disease Research Branch, National Human Genome Research Institute; Veterinary Resources Program, Office of Research Services; National Institute on Aging, National Institutes of Health, Bethesda, MD 20892; and Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, One..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carrolee","family":"Barlow","sequence":"additional","affiliation":[{"name":"Experimental Immunology Branch, Genetics Department, and Biostatistics and Data Management Section, Office of the Director of the Division of Clinical Sciences, National Cancer Institute; Genetic Disease Research Branch, National Human Genome Research Institute; Veterinary Resources Program, Office of Research Services; National Institute on Aging, National Institutes of Health, Bethesda, MD 20892; and Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, One..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhuna","family":"Shen","sequence":"additional","affiliation":[{"name":"Experimental Immunology Branch, Genetics Department, and Biostatistics and Data Management Section, Office of the Director of the Division of Clinical Sciences, National Cancer Institute; Genetic Disease Research Branch, National Human Genome Research Institute; Veterinary Resources Program, Office of Research Services; National Institute on Aging, National Institutes of Health, Bethesda, MD 20892; and Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, One..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Eckhaus","sequence":"additional","affiliation":[{"name":"Experimental Immunology Branch, Genetics Department, and Biostatistics and Data Management Section, Office of the Director of the Division of Clinical Sciences, National Cancer Institute; Genetic Disease Research Branch, National Human Genome Research Institute; Veterinary Resources Program, Office of Research Services; National Institute on Aging, National Institutes of Health, Bethesda, MD 20892; and Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, One..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth M.","family":"Steinberg","sequence":"additional","affiliation":[{"name":"Experimental Immunology Branch, Genetics Department, and Biostatistics and Data Management Section, Office of the Director of the Division of Clinical Sciences, National Cancer Institute; Genetic Disease Research Branch, National Human Genome Research Institute; Veterinary Resources Program, Office of Research Services; National Institute on Aging, National Institutes of Health, Bethesda, MD 20892; and Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, One..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Ried","sequence":"additional","affiliation":[{"name":"Experimental Immunology Branch, Genetics Department, and Biostatistics and Data Management Section, Office of the Director of the Division of Clinical Sciences, National Cancer Institute; Genetic Disease Research Branch, National Human Genome Research Institute; Veterinary Resources Program, Office of Research Services; National Institute on Aging, National Institutes of Health, Bethesda, MD 20892; and Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, One..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Wynshaw-Boris","sequence":"additional","affiliation":[{"name":"Experimental Immunology Branch, Genetics Department, and Biostatistics and Data Management Section, Office of the Director of the Division of Clinical Sciences, National Cancer Institute; Genetic Disease Research Branch, National Human Genome Research Institute; Veterinary Resources Program, Office of Research Services; National Institute on Aging, National Institutes of Health, Bethesda, MD 20892; and Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, One..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Hodes","sequence":"additional","affiliation":[{"name":"Experimental Immunology Branch, Genetics Department, and Biostatistics and Data Management Section, Office of the Director of the Division of Clinical Sciences, National Cancer Institute; Genetic Disease Research Branch, National Human Genome Research Institute; Veterinary Resources Program, Office of Research Services; National Institute on Aging, National Institutes of Health, Bethesda, MD 20892; and Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, One..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2000,6,6]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1159\/000472285"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7792600"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.15.1.177"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V87.2.423.bloodjournal872423"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80086-0"},{"key":"e_1_3_3_6_2","first-page":"4211","volume":"10","author":"Xu Y","year":"1996","unstructured":"Y Xu, T Ashley, E E Brainerd, R T Bronson, M S Meyn, D Baltimore Genes Dev 10, 4211\u20132422 (1996).","journal-title":"Genes Dev"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.23.13084"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.10.1246"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.19.4.3095"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90029-C"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/333742a0"},{"key":"e_1_3_3_12_2","volume-title":"Histopathological Methods and Color Atlas of Special Stains and Tissue","author":"Luna L G","year":"1992","unstructured":"L G Luna Histopathological Methods and Color Atlas of Special Stains and Tissue (American Histolabs, Inc. 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