[en] INTRODUCTION: Whole body fractionated irradiation induces thymic lymphomas in C57BL/Ka mice after a latent period during which preleukemic cells progressively transform into leukemic cells within an abnormal thymic microenvironment. A bone marrow graft or repeated cytokine injections prevent lymphoma development. We think that these treatments restore altered mechanisms controlling apoptosis. MATERIALS AND METHODS: Apoptosis was analyzed by flow cytometry in thymocytes from different groups of mice (control, preleukemic, prevented mice). RESULTS: The apoptotic rates did not change in freshly isolated thymocytes from different experimental groups. However, after culture, the level of apoptosis increased in preleukemic thymuses; and returned to normal value in cultured thymocytes from irradiated mice after lymphoma preventing treatments. Furthermore, thymic microenvironmental factors can control thymocyte apoptosis. CONCLUSION: We propose that after leukemogenic irradiation, there is an increase of cells with an activated suicide program, but that alterations of thymic environmental factors rescue them from apoptosis, allowing their further neoplastic transformation.
Kaplan HS: On the natural history of the murine leukemia. Cancer Res 27: 1325-1340, 1967.
Haran-Ghera N, Rubio N, Leef F and Goldstein G: Characteristics of preleukemia cells induced in mice. Cell Immunol 37: 308-314, 1978.
Defresne MP, Rongy AM, Greimers R and Boniver J: Cellular aspects of radiation leukemogenesis in C57 BL/Ka mice II-Thymic microenvironment and thymic nurse cells. Leukemia Res 10: 783-789, 1986.
Rongy AM, Humblet C, Lelievre C, Greimers R, Defresne MP and Boniver J: Abnormal thymocyte subpopulations in split dose irradiated C57 BL/Ka mice before the onset of lymphomas. Effects of bone marrow grafting. Thymus 16: 7-27, 1990.
Sen-Majumdar A, Guidos C, Kina T, Lieberman M and Weissman IL: Characterization of preneoplastic thymocytes and their neoplastic progression in irradiated C57 BL/Ka mice. J Immunol 153: 1581-1592, 1994.
Defresne MP, Greimers R, Lenaerts P and Boniver J: Effects of marrow grafting on preleukemic cells and thymic nurse cells in C57 BL/Ka mice after a leukemogenic split dose irradiation. J Natl Cancer Inst 77: 1079-1085, 1986.
Boniver J, Humblet C and Defresne MP: Tumor necrosis factor and Interferon gamma inhibit the development of radiation-induced thymic lymphomas in C57 BL/Ka mice. Leukemia 3: 611-613, 1989.
Humblet C, Greimers R, Delvenne P, Deman J, Boniver J and Defresne MP: Prevention of murine radiogenic thymic lymphomas by tumor necrosis factor or by marrow grafting. J Natl Cancer Inst 88: 824-831, 1996.
Robey E and Fowlkes BJ: Selective events in T cell development. Ann Rev Immunol 12: 675-705, 1994.
Egerton M, Scollay R and Shortman K: Kinetics of mature T-cell development in the thymus. Proc Natl Acad Sci USA 87: 2579-2582, 1990.
Villa-Verde DM, Defresne MP, Greimers R, Dardenne M, Savino W and Boniver J: Induction of thymocyte proliferation by supernatants from a mouse thymic epithelial cell line. Cell Immunol 136: 113-121, 1991.
Taniyama T, Kinoshita Y, Hato F Tominaga K, Kimura S and Itoh T: Separation of rosette formation-inducing polypeptides from the supernatant of cultures of rat thymic epithelial cell line. Cell Mol Biol 35: 535-545, 1989.
Nicoletti I, Migliorati G, Pagliacci MC, Grignani F and Riccardi C: A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods 139: 271-279, 1991.
Wyllie AH: Apoptosis and the regulation of cell numbers in normal and neoplastic tissues: an overview. Cancer Metastasis 11: 95-103, 1992.
Majno G and Joris I: Apoptosis, Oncosis, and Necrosis. An Overview of cell death. Am J Pathol 146: 3-15, 1995.
Surth CD and Sprent J: T-cell apoptosis detected in situ during positive and negative selection in the thymus. Nature 372: 100-103, 1994.
Cohen GM, Sun XM, Snowden RT, Ormerod MG and Dinsdale D: Identification of a transitional preapoptotic population of thymocytes. J Immunol 151: 566-574, 1993.
Cohen GM, Sun XM, Fearnhead H, MacFarlane M, Brown DG, Snowden RT and Dinsdale D: Formation of large molecular weight fragments of DNA is a key committed step of apoptosis in thymocytes. J Immunol 153: 507-516, 1994.
Sprecher E, Giloh H, Rahamin E, Yefenof E and Becker Y: Cytofluorometric analysis of thymic interdigitating cells from C57BL/6 mice prior and after leukemogenic x-irradiation. Leuk Res 13: 799-809, 1989.
Strzadala L, Miazek A, Matuszyk J and Kisielow P: Role of thymic selection in the development of thymic lymphomas in TCR transgenic mice. Int Immunol 9: 127-138, 1997.
Boniver J, Humblet C, Delvenne P, Deman J, Rongy AM, Greimers R and Defresne MP: TNF-α and radiation-induced thymic lymphomas. Leukemia 6: 83S-84S, 1992.