DOI: 10.1073/pnas.97.12.6664. Recombinase-activating gene (RAG) 2-mediated V(D)J recombination is not essential for tumorigenesis in <i>Atm</i> -deficient mice

Recombinase-activating gene (RAG) 2-mediated V(D)J recombination is not essential for tumorigenesis in Atm -deficient mice

10.1073/pnas.97.12.6664

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

The majority of Atm -deficient mice die of malignant thymic lymphoma by 4–5 mo of age. Cytogenetic abnormalities in these tumors are consistently identified within the Tcr α/δ 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 Rag2 −/− Atm −/− 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 Atm −/− mice is not prevented by loss of RAG-2 and thus is not dependent on V(D)J recombination. Malignant thymic lymphomas in Rag2 −/− Atm −/− mice occurred at a lower frequency and with a longer latency as compared with Atm −/− mice. Importantly, cytogenetic analysis of these tumors indicated that multiple chromosomal abnormalities occurred in each tumor, but that none of these involved the Tcr α/δ locus. Nonmalignant peripheral T cells from TCR-transgenic Rag2 −/− Atm −/− 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 Atm −/− 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 Atm -deficient thymocytes are susceptible to developing chromosome aberrations that predispose to malignant transformation.

Bibliography

Petiniot, L. K., Weaver, Z., Barlow, C., Shen, R., Eckhaus, M., Steinberg, S. M., Ried, T., Wynshaw-Boris, A., & Hodes, R. J. (2000). Recombinase-activating gene (RAG) 2-mediated V(D)J recombination is not essential for tumorigenesis in Atm -deficient mice. Proceedings of the National Academy of Sciences, 97(12), 6664â6669.

Authors 9

Lisa K. Petiniot (first)
Zoë Weaver (additional)
Carrolee Barlow (additional)
Rhuna Shen (additional)
Michael Eckhaus (additional)
Seth M. Steinberg (additional)
Thomas Ried (additional)
Anthony Wynshaw-Boris (additional)
Richard J. Hodes (additional)

References 23 Referenced 63

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10.1016/S0092-8674(00)80086-0
Y Xu, T Ashley, E E Brainerd, R T Bronson, M S Meyn, D Baltimore Genes Dev 10, 4211–2422 (1996). / Genes Dev by Xu Y (1996)
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10.1101/gad.13.10.1246
10.1128/MCB.19.4.3095
10.1016/0092-8674(92)90029-C
10.1038/333742a0
L G Luna Histopathological Methods and Color Atlas of Special Stains and Tissue (American Histolabs, Inc. Publications Division, Gaithersburg, MD, 1992). / Histopathological Methods and Color Atlas of Special Stains and Tissue by Luna L G (1992)
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Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:38 a.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 5:08 p.m.)
Indexed	1 year, 1 month ago (July 16, 2024, 9:40 p.m.)
Issued	25 years, 2 months ago (June 6, 2000)
Published	25 years, 2 months ago (June 6, 2000)
Published Online	25 years, 2 months ago (June 6, 2000)
Published Print	25 years, 2 months ago (June 6, 2000)

Funders 0

None

BibTeX

@article{Petiniot_2000, title={Recombinase-activating gene (RAG) 2-mediated V(D)J recombination is not essential for tumorigenesis in Atm -deficient mice}, volume={97}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.97.12.6664}, DOI={10.1073/pnas.97.12.6664}, number={12}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Petiniot, Lisa K. and Weaver, Zoë and Barlow, Carrolee and Shen, Rhuna and Eckhaus, Michael and Steinberg, Seth M. and Ried, Thomas and Wynshaw-Boris, Anthony and Hodes, Richard J.}, year={2000}, month=jun, pages={6664–6669} }

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