Oncogenic potential of cyclin E in T-cell lymphomagenesis in transgenic mice: evidence for cooperation between cyclin E and Ras but not Myc

To study the oncogenic activity of cyclin E in an ill vivo system we genera ted transgenic mice expressing high levels of cyclin Ii: in T-lymphocytes b y using a construct containing the CD2 locus control region. These animals were neither predisposed to develop any tumors spontaneously nor showed an increased incidence when crossbred with E mu L-myc transgenic mice but deve loped hyperplasia in peripheral lymphoid organs at later age with an incide nce of 27%. When treated with the DNA methylating carcinogen N-methylnitros ourea (MNU) that provokes the development of T-cell lymphomas, CD2-cyclin E transgenic animals came down with T-cell neoplasia showing a significant h igher incidence (54%) than normal non transgenic controls (31%). In one of eight tumors that arose in normal MNU treated mice me could find an expecte d activating point mutation in the Ki-ras gene (12.5%). In contrast, the sa me mutation occurred in five of 16 tumors from CD2-cyclin E transgenic mice (31.2%). Whereas cyclin E overexpression alone did not lead to an increase d CDK2 activity we observed in ail tumors that emerged from either MNU trea ted normal mice or treated CD2-cyclin E transgenics a downregulation of p27 (KIP1) and a higher histone HI kinase activity: in CDK2 immunoprecipitates compared to normal tissue. These findings demonstrate that high level expre ssion of cyclin E can predispose T-cells for hyperplasia and malignant tran sformation. However, the results also suggest that this activity of cyclin E is manifest only when other cooperating oncogenes in particular I as gene s are present and activated. This would be consistent with our previous fin ding that cyclin E and Ha-Ras cooperate in focus formation assays in rat em bryo fibroblasts.