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

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

M J Liao et al. Genes Dev. 1999.

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.

PubMed Disclaimer

Figures

Figure 1

Figure 1

Rag-1 is required for thymic lymphoma development in _Atm_−/− mice. Tumor-free survival of mice is plotted with time. Each data point represents the sacrifice or death of a terminally ill mouse. A drop in percentage reflects the sacrifice or death of a mouse with thymoma. As with _Atm_−/− mice (□; n = 8), 100% of the Atm_−/−_Rag-1+/− mice (⋄; n = 5) developed thymic lymphoma. The mean survival time was 4.8 months for _Atm_−/− mice and 4.7 months for Atm_−/−_Rag-1+/− mice. All _Atm_−/−_Rag-1_−/− mice (○; n = 9) died or were sacrificed with no overt thymic lymphoma or other tumors. The mean survival time was 9 months, comparable to _Rag-1_−/− mice housed under the same conditions. Three of the nine _Atm_−/−_Rag-1_−/− mice died of pneumonia at 5–6 months with no sign of thymic lymphoma. Mouse food containing antibiotics was used to treat one _Atm_−/−_Rag-1_−/− mouse of this data set with similar symptoms.

Figure 2

Figure 2

_Rag-1_−/− thymocyte differentiation is rescued by a TCR transgene. (A) CD4/CD8 expression was analyzed by FACS (Materials and Methods). _Atm_−/−_Rag-1_−/− thymocytes (_Atm_−/−_R1_−/−) are blocked at the CD4−CD8− DN stage compared to wild-type (WT) thymocytes. Expression of LCMV–TCR transgenes in _Atm_−/−_Rag-1_−/− thymocytes (Atm_−/−_TCR+_R1_−/−) induced a CD4+CD8+ DP population. The Atm_−/−_TCR+ thymocyte population is shown as a control. TCR+ thymocytes have the same profile as those from Atm_−/−_TCR+ mice (not shown). (B) Lack of positive thymic selection is not a factor in thymoma inhibition. Most of the Atm_−/−_TCR+_Rag-1_−/− mice are H-2Db positive, and have mature T cells in peripheral blood. Atm_−/−_TCR+_R1_−/− mice were screened for the presence of the H-2Db MHC molecule and the TCR component CD3 using PBLs (Materials and Methods). Profiles of PBLs from C57BL6 and DBA2 mice are shown as positive and negative controls for the presence of H-2Db, respectively. One typical profile of the seven Atm_−/−_TCR+_R1_−/− PBLs is shown, which confirms H-2Db-positive and CD3-positive (mature) T cells. An _Atm_−/−_R1_−/− PBL profile serves as the negative control for CD3 expression of mature T cells.

Figure 3

Figure 3

V(D)J recombination is required for Atm-deficient thymoma. All _Atm_−/− mice (□; n = 8) and Atm_−/−_TCR+Rag-1+/− mice (⋄; n = 12) died of thymic lymphoma with a mean survival time of 4.8 and 5.0 months, respectively. Of the Atm_−/−_TCR+_Rag-1_−/− mice shown (○; n = 9), 6 died of infections at 6–9 months (mean survival, 8 months) with no sign of thymic lymphoma. Others are currently alive at 8 months with no sign of lymphoma. Because Atm_−/−_TCR+Rag-1+/− and Atm_−/−_TCR+_Rag-1_−/− mice are from the same cross, genetic background does not contribute to the observed difference.

References

    1. Agrawal A, Eastman QM, Schatz DG. Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system. Nature. 1998;394:744–751. -PubMed
    1. Banin S, Moyal L, Shieh S, Taya Y, Anderson CW, Chessa L, Smorodinsky NI, Prives C, Reiss Y, Shiloh Y, Ziv Y. Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science. 1998;281:1674–1677. -PubMed
    1. Barlow C, Hirotsune S, Paylor R, Liyanage M, Eckhaus M, Collins F, Shiloh Y, Crawley JN, Ried T, Tagle D, Wynshaw-Boris A. Atm-deficient mice: A paradigm of Ataxia Telangiectasia. Cell. 1996;86:159–171. -PubMed
    1. Barlow C, Brown K, Deng C, Tagle D, Wynshaw-Boris A. Atm selectively regulates distince p53-dependent cell-cycle checkpoint and apoptotic pathways. Nat Genet. 1997;17:453–456. -PubMed
    1. Canman CE, Lim DS, Cimprich KA, Taya Y, Tamai K, Sakaguchi K, Appella E, Kastan MB, Siliciano JD. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science. 1998;281:1677–1679. -PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources