EXPRESSION OF A PIM-1 TRANSGENE ACCELERATES LYMPHOPROLIFERATION AND INHIBITS APOPTOSIS IN LPR LPR MICE

Transgenic mice expressing the Pim-1 kinase are predisposed to develop T-cell lymphomas with a long latency period of about 7-9 months. Howe ver, the exact functional basis of the oncogenic activity of Pim-1 rem ains obscure. C57BL/6 mice homozygous for the lpr mutation develop a w ell-described lymphoproliferative syndrome at about 26-30 weeks of age . This syndrome is characterized mainly by the accumulation of abnorma l T cells in lymph nodes because of the lack of Fas receptor-induced a poptosis. We find that backcross of Emu-Pim-1 transgenics (mice with a transgene that carries the mouse Pim-1 gene under the transcriptional control of the immunoglobulin heavy chain gene enhancer Emu) into lpr /lpr mice results in strong acceleration of lymphoproliferation and dr amatic enlargement of lymph nodes. In addition, we show here that cult ured lymph node cells from Emu-Pim-1 lpr/lpr mice are rescued from rap id apoptosis that normally occurs in nontransgenic lpr cells in vitro. We also present evidence that CD4+/CD8+ double-positive thymocytes fr om lpr/lpr mice are sensitive to dexamethasone-induced apoptosis, alth ough lpr/lpr mice lack the Fas receptor. In contrast, Emu-Pim-1 lpr/lp r animals show considerable protection from dexamethasone-induced apop tosis. These results show that Pim-1 can strongly accelerate lymphopro liferation through inhibition of apoptosis and thereby provide first i nsight into the functional basis for the oncogenic activity of Pim-1.