Cwv. Vanoordt et al., X-RAY-INDUCED LYMPHOMAGENESIS IN E-MU-PIM-1 TRANSGENIC MICE - AN INVESTIGATION OF THE COOPERATING MOLECULAR EVENTS, Carcinogenesis, 19(5), 1998, pp. 847-853
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.