Dysfunction of Stat4 leads to accelerated incidence of chemical-induced thymic lymphomas in mice.

Stat4 (signal transducer and activator of transcription) can be activated by specific cytokines, such as IL-12, IFN-alpha, and IL-2. Since IL-12 has been implicated in tumor surveillance and cancer treatment, we hypothesized that its signaling mediator, Stat4, may repress tumor growth. Mice lacking Stat4 allowed us to directly assess the role of Stat4 in tumor surveillance. Lymphomas were chemically induced by MNU (N-methyl-N-nitrosourea) injection in Stat4-deficient or wild-type control mice. At the time of termination of the experiment 16 weeks after injection, 78% of homozygous Stat4-deficient mice had developed thymic lymphomas. This tumor induction was dramatically higher than in heterozygous (14%) and wild-type controls (14%). Lymphoma development occurred 5 weeks earlier in homozygous knockout mice than in other genotypes. Mice bearing tumors were fragile and had an increased death rate in the early stages of the experiment. The tumors displayed a very aggressive phenotype with metastases in multiple organs. Therefore, the loss of Stat4 predisposes mice to tumor induction and demonstrates crucial roles of Stat4 in the prevention of tumors. Copyright 2001 Academic Press.