Critical role for Atm in suppressing V(D)J recombination-driven thymic lymphoma

Abstract

Chromosome translocations involving T cell receptor (TCR) loci have been found in tumors from Ataxia telangiectasia (AT) patients and in mouse Atm−/− thymoma, suggesting the involvement of V(D)J recombination in these malignancies. By introducing a RAG-1 deficiency into Atm −/− mice in the presence of a TCR transgene, we show that V(D)J recombination is critical for thymoma development in these mice. Therefore, aberrant V(D)J recombination, normally suppressed by Atm, facilitates tumorigenic events leading to cancer. Because V(D)J recombination is dispensable for lymphomagenesis upon p53 deficiency, this study also indicates that Atm and p53 function by distinct mechanisms in suppressing thymoma. Received February 17, 1999; revised version accepted April 1, 1999. Chromosome translocations have been found in many lymphoid malignancies, resulting in activation of protooncogenes in those cells (Rabbitts 1994;Nowell 1997). In many cases, the breakpoints of translocations involve immunoglobulin or T cell receptor (TCR) loci, suggesting a predisposition by these loci to the oncogenic events. V(D)J recombination assembles immunoglobulin and TCR gene segments via double-strand break (DSB) intermediates and is active at immunoglobulin and TCR loci during B and T cell development, respectively (Lewis 1994). It has long been hypothesized that errors in this process provide a major source of chromosome translocations in lymphoid malignancies (for review, see Danska and Guidos 1997;Kirsch and Lista 1997). However, the molecules involved in regulating this process to suppress cancer proneness are not understood.Ataxia telangiectasia (AT), caused by mutations in the ATM gene, is a recessive chromosomal instability disease with pleiotropic phenotypes (Lavin and Shiloh 1997). AT patients have a high risk of cancer, particularly lymphoid malignancies. Chromosome translocations involving the TCR locus occur at a high frequency in AT T-lymphoid tumors (for review, see Taylor et al. 1996;Kirsch 1994). Furthermore, thymic lymphoma also develops in Atm-deficient mice, and evidence for TCRassociated rearrangements within tumors has been demonstrated (Barlow et al. 1996;Elson et al. 1996;. These observations suggest that the tumor suppressor function of ATM acts through a mechanism involving V(D)J recombination. To test this hypothesis, we have analyzed the effect on tumorigenesis of inactivating V(D)J recombination in Atm-deficient mice. Here, by introducing a recombination activating gene (RAG)-1 deficiency into Atm −/− mice, we show that V(D)J recombination is a critical step in thymic lymphoma development, thus identifying a critical role for Atm in suppressing such tumorigenic events in the T-cell lineage. Results Recombination-activating genes (RAG), Rag-1+/− were littermates (Materials and Methods), mouse background differences other than indicated deficiencies did not contribute to the inhibition of thymoma. Thus, prevention of V(D)J recombination by Rag-1 deficiency blocked tumorigenesis in Atm-deficient mice.As a result o...

Ataxia-Telangiectasia Mutated Is Not Required for p53 Induction and Apoptosis in Irradiated Epithelial Tissues

“…Two possibilities are as follows: a unique role of Atm in lymphoid lineages or a specific lack of redundant pathways to Atm in lymphoid tissue, which would expose the vulnerability of Atm loss. Liao and Van Dyke (43) concluded that there were two different mechanisms of tumor suppression by Atm and p53. Lymphoma suppression in Atm-null mice depended on V(D)J recombination, whereas lymphomas from p53-null mice arose independent of V(D)J recombination.…”

The loss of the BH3-only Bcl-2 family member Bid delays T-cell leukemogenesis in Atm−/− mice

“…Rag À / À Atm À / À mice do not develop leukemia, underscoring the importance of recombination to Atm À / À leukemogenesis. 25 Bid has been reported to be important for cell death in DN3 thymocytes. 27 Bid transcription is stimulated by p53 in DN3 cells.…”

“…Loss of the Rag recombinase abrogates leukemia development in Atm À / À mice. 25 We reasoned that if Bid has a pro-apoptotic role in the Atm-directed DDR, loss of Bid in addition to Atm might accelerate leukemogenesis by allowing propagation of oncogenic mutations. If Bid functions solely as an Atm effector, Bid À / À Atm À / À mice should phenocopy Atm À / À mice.…”

Aberrantly resolved RAG-mediated DNA breaks in Atm-deficient lymphocytes target chromosomal breakpoints incis

“…In this regard, deficiency in the ataxia telangiectasia mutated (ATM) serine threonine kinase in both mice and humans leads to an increased incidence of lymphoid tumors with RAG-dependent translocations involving antigen receptor loci (17)(18)(19)(20)(21). In addition, mature, nontransformed Atm-deficient lymphocytes have an increased frequency of translocations and other chromosomal aberrations involving antigen receptor loci (18,19,(22)(23)(24).…”