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Updated: Aug 6, 2026
Derivation of Thymic Lymphoma T-cell Lines from Atm-/- and p53-/- Mice
Published on: April 3, 2011
Dysfunction of Stat4 leads to accelerated incidence of chemical-induced thymic lymphomas in mice
1Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, 06520-8023, USA.
Abstract:
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.
Insights
The signal transducer and activator of transcription 4 (Stat4) plays a crucial role in preventing tumor development. Mice lacking Stat4 showed a significantly higher incidence and earlier onset of aggressive lymphomas.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Signal transducer and activator of transcription 4 (Stat4) is activated by cytokines like IL-12, IFN-alpha, and IL-2.
- Interleukin-12 (IL-12) is involved in tumor surveillance and cancer treatment.
- Stat4's role in tumor repression was hypothesized due to its mediation of IL-12 signaling.
Purpose of the Study:
- To investigate the role of Stat4 in tumor surveillance and prevention.
- To determine if Stat4 deficiency predisposes to tumor development.
Main Methods:
- Chemically induced lymphomas using N-methyl-N-nitrosourea (MNU) in Stat4-deficient and wild-type mice.
- Monitoring tumor development and incidence over 16 weeks.
- Assessing tumor aggressiveness, metastasis, and survival rates.
Main Results:
- 78% of homozygous Stat4-deficient mice developed thymic lymphomas, compared to 14% in heterozygous and wild-type controls.
- Lymphoma onset was approximately 5 weeks earlier in Stat4-deficient mice.
- Tumors in knockout mice were aggressive, showed widespread metastases, and were associated with increased mortality.
Conclusions:
- Loss of Stat4 significantly predisposes mice to chemically induced tumor development.
- Stat4 plays a critical role in the prevention of aggressive lymphomas.
- These findings highlight Stat4 as a key mediator in tumor suppression.
