EXPRESSION OF LYMPHOMAGENIC ONCOGENES IN T-CELL LYMPHOMAS OF HPV-16 TRANSGENIC MICE

We have previously established that a dimer repeat of the complete HPV 16 genome is sufficient to cause multiple organ malignancies, either carcinomas or T-cell lymphomas, in transgenic mice. Here, we report th e expression of oncogenes supporting the notion that these tumors aros e via multiple oncogenic pathways. In these mice, the transgenic HPV 1 6 genome cosegregated with the tumor phenotype. E6/E7 expression was o bserved in both carcinomas and T-cell lymphomas, while E2 expression w as observed only in T-cell lymphomas. Some of the T-cell lymphomas rev ealed E2 expression alone, implying that oncogenic pathways of HPV oth er than the one involving E6/E7 existed in these transgenic mice. To e stablish that this is the case, expression of genes downstream from E6 /E7 and oncogenes involved in T-cell lymphoma formation were analyzed. p53 mutations were observed in two of five tumors that lacked E6 expr ession. High levels of c-myc gene expression were observed in five of six tumors with E7 expression, suggesting that a pathway involving E7, inactivation of Rb, and activation of c-myc is important in tumorigen esis of HPV 16 in these transgenic animals. High levels of expression of the c-Pim gene were also noted in two of three c-myc-expressing T-c ell lymphomas, suggesting cooperation between these two proto-oncogene s. Activation of Hox-ii, Tal2/SCL-2, and Rbtn1/Ttg1 expression, which are highly associated with human T-cell acute lymphoblastic leukemia ( T-ALL), was observed in three of three T-cell lymphomas with E2 expres sion but not E6/E7 expression, showing that pathways to tumor formatio n not involving E6/E7 exist in these transgenic animals. At least two oncogenic pathways to tumors in HPV 16 transgenic mice exist, one invo lving E6/E7 and c-myc and the other involving E2 and lymphomagenic onc ogenes.