Very high frequency of lymphoma induction by a chemical carcinogen in pim-1 transgenic mice

Abstract

Infection of mice with Moloney murine leukaemia virus (MuLV) induces T-cell lymphomas after an average latency period of 150 days. In these lymphomas the MuLV DNA is frequently integrated into the mouse chromosomal DNA in the vicinity of the pim-1 oncogene. Transgenic mice overexpressing the pim-1 oncogene are predisposed to develop T-cell lymphomas, but only to the extent that approximately 10% of the mice develop a lymphoma within 240 days. When these mice are infected with MuLV, lymphomas develop in all mice in only 50-60 days. In these lymphomas MuLV DNA is integrated near either the c-myc or N-myc gene, suggesting that pim-1 and myc synergize in lymphomagenesis. To determine whether this system has a more general application, we have now tested the susceptibility of pim-1 transgenic mice to N-ethyl-N-nitrosourea (ENU), a chemical carcinogen. With a single low dose of ENU, nearly all pim-1 transgenic mice, but only 15% of non-transgenic mice, develop T-cell lymphomas within 200 days. All ENU-induced lymphomas in both pim-1 transgenic and non-transgenic mice express high levels of c-myc messenger RNA, supporting the notion that pim-1 and c-myc synergize in lymphoma induction. We propose that pim-1 transgenic mice could be used to test the oncogenic potential of other chemical compounds.

Potentiation of lymphomagenesis by methylnitrosourea in mice transgenic for LMO1 is blocked by O6-alkylguanine DNA-alkyltransferase

“…During the latent period, additional genetic changes may be required to convert the proliferating thymocyte to a malignant cell. This process may be similar to those observed in murine lymphomas induced by chemicals (Newcombe et al, 1988;Breuer et al, 1991;Corominas, et al, 1991), oncogenes (Breuer et al, 1991;Lindeman al., 1994;Linette et al, 1995), or tumor suppressor gene mutant mice (Donehower et al, 1992;Angel et al, 1993;Elson et al, 1995).…”

“…MNU also increased the incidence of mammary tumors in mice transgenic for MMTV-N-ras (Mangues et al, 1994). Likewise, ethylnitrosourea increases lymphomagenesis in pim-1 transgenic mice through myc overexpression and, in 10% of cases, K-ras mutations (Breuer et al, 1991). In a skin tumor initiation/promotion model, heterozygotic p53 knockout mice had an increased incidence of carcinomas but a similar incidence of papillomas following MNU exposure, suggesting a role for the heterozygotic state of p53 in cancer promotion but not initiation (Kemp et al, 1993).…”

Developmental expression of Pim kinases suggests functions also outside of the hematopoietic system

“…This suggested that overexpression of the pim-1 gene by itself was insu cient for cell transformation. Accordingly, when Em-pim-1 mice were exposed to viral or chemical carcinogenic agents, the development of lymphomas was accelerated Breuer et al, 1989). In most cases, this correlated with activation of one of the myc family oncogenes.…”

Role of Pim-1 in Smooth Muscle Cell Proliferation

“…Its expression is induced by a variety of cytokines, growth factors, and mitogens (17)(18)(19), suggesting that Pim-1 may be an important intermediate in signal transduction. In hematopoietic cells, Pim-1 cooperates with c-Myc (20,21) and enhances the transcription activity of c-Myb (22,23). It has also been shown that Pim-1 activates the cyclin-dependent kinase inhibitor p21 (24) and that the antiapoptotic factor Bcl-2 is regulated downstream of Pim-1 (25), suggesting that Pim-1 is involved in cell cycle regulation and apoptosis in hematopoietic cells.…”