X-RAY-INDUCED LYMPHOMAGENESIS IN E-MU-PIM-1 TRANSGENIC MICE - AN INVESTIGATION OF THE COOPERATING MOLECULAR EVENTS

Transgenic mice overexpressing the pim-l oncogene in their lymphoid co mpartment display a low incidence of spontaneous T-cell lymphomas, but are highly susceptible to point mutation-inducing genotoxic carcinoge ns. We show here that total body X-irradiation, which causes mainly ch romosomal deletions, rearrangements and amplifications, significantly enhances lymphoma development in E mu-pim-1 transgenic mice, The X-ray -induced E mu-pim-1 and nontransgenic lymphomas have a comparable high cell turnover as shown by a relatively high S-phase fraction and a hi gh apoptotic activity. Consistent with previous observations, in 75% o f all lymphomas c-myc mRNA levels are 5-to 20-fold higher than in cont rol, non-lymphomatus spleen/thymus, The expression of other oncogenes, which have previously found to be activated in combination with pim-1 in lymphomagenesis, such as gfi-1/pal-1,frat-l and tiam-1, and also o f the mdm-2 and mdm-x oncogenes, appeared not to be affected. Deletion s and/or rearrangements of the p16(INK4A) and p15(INK4B) tumor suppres sor genes were seldom observed tin three out of 92 X-ray-induced lymph omas), Strikingly, in addition to the high mRNA levels of the pim-1 tr ansgene, the levels of the endogenous pim-1 transcripts were elevated significantly in 16% of the X-ray-induced E mu-pim-1 lymphomas compare d with control spleen, even surpassing the level of the pim-1 transgen e mRNA by 3-to 5-fold. In combination with previous results, which sho wed that the lymphoma incidence increased concordantly with higher lev els of pim-1, this supports the notion that pim-l can contribute to ly mphomagenesis in a dose-dependent manner.