Carcinogenesis, Vol 19, 847-853, Copyright © 1998 by Oxford University Press
CW van der Houven van Oordt, TG Schouten, JH van Krieken, JH van Dierendonck, AJ van der Eb and ML Breuer
Transgenic mice overexpressing the pim-1 oncogene in their lymphoid
compartment display a low incidence of spontaneous T-cell lymphomas, but
are highly susceptible to point mutation-inducing genotoxic carcinogens. We
show here that total body X-irradiation, which causes mainly chromosomal
deletions, rearrangements and amplifications, significantly enhances
lymphoma development in E mu-pim-1 transgenic mice. The X-ray-induced E
mu-pim-1 and non-transgenic lymphomas have a comparable high cell turnover
as shown by a relatively high S-phase fraction and a high apoptotic
activity. Consistent with previous observations, in 75% of all lymphomas
c-myc mRNA levels are 5- to 20- fold higher than in control,
non-lymphomatous 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-1 and tiam-1, and also of the
mdm-2 and mdm-x oncogenes, appeared not to be affected. Deletions and/or
rearrangements of the p16INK4A and p15INK4B tumor suppressor genes were
seldom observed (in three out of 92 X-ray-induced lymphomas). Strikingly,
in addition to the high mRNA levels of the pim-1 transgene, the levels of
the endogenous pim-1 transcripts were elevated significantly in 16% of the
X-ray-induced E mu-pim-1 lymphomas compared with control spleen, even
surpassing the level of the pim-1 transgene mRNA by 3- to 5-fold. In
combination with previous results, which showed that the lymphoma incidence
increased concordantly with higher levels of pim-1, this supports the
notion that pim-1 can contribute to lymphomagenesis in a dose-dependent
manner.
ARTICLES
X-ray-induced lymphomagenesis in E mu-pim-1 transgenic mice: an investigation of the co-operating molecular events
MGC-Department of Molecular Cell Biology, Leiden University, The Netherlands.
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