CPB 69700 RESEARCH
SEMINAR
Michael R. Logan, DVM
CPB Graduate Student in Interdisciplinary
Comparative Medicine Graduate
Program
“Demonstration Of
Peripheral T-Cell Lymphoma In BATF And BATF3 Transgenic Mice”
Thurs., April 9, 2009
VPTH 112
- 3:30 pm
ABSTRACT:
The AP-1 transcription factor is comprised of dimerizing basic leucine zipper (bZIP) proteins and plays a critical role in multiple cellular processes, including growth, development, differentiation and apoptosis. Therefore, it is not surprising that AP-1 dysregulation is a common feature of clinical conditions such as neurological disorders and cancer. A thorough understanding of how AP-1 activity is regulated in vivo will yield new insight into carcinogenesis and possibly define novel therapeutic targets for cancer treatment.
The BATF family of bZIP proteins participates in AP-1 dimers that have been shown to repress AP-1 mediated gene expression. BATF1 and BATF3 are the best characterized BATF family members and both are expressed in lymphoid cells of humans and mice. To examine how the overexpression of these natural AP-1 inhibitors could impact the growth and development of the murine immune system, our lab generated transgenic mice in which either BATF1 or BATF3 are constitutively expressed in T-cells using a CD2 promoter expression cassette. The resulting mice are viable and show no gross alternations in the development of the major T-cell subsets. However, both lines of mice show impaired development of a minor, yet immunologically important, T-cell subset referred to as natural killer T (NKT) cells. As a severe deficiency in NKT cells has been linked to a depressed anti-tumor response in other models, it was logical to investigate if subtle T-cell growth defects predicated by the overexpression BATF proteins could, in the absence of NKT cells, result in increased cancer incidence.
BATF1 and BATF3 transgenic mice of advanced age developed clinical signs including weight loss and enlargement of peripheral lymph nodes. At one year of age, sex and age matched transgenic and non-transgenic littermates were sacrificed, necropsied, and subjected to histopathologic examination. The majority of BATF1 and BATF3 transgenic mice had diagnosis of lymphoma in at least one organ. Mesenteric lymph nodes were most commonly affected. Other organs affected by lymphoma included spleen, pancreas, and liver. Biopsy sections from each transgenic mouse were subjected to immunohistochemistry. All examined tumor sections expressed CD3 and lacked significant CD79a immunoreactivity, indicating T-cell origin of the neoplastic cells.
Though increased AP-1 transcriptional activity has been described for several cancers, our findings suggest that chronic suppression of AP-1 activity can promote the development of peripheral T-cell lymphoma. Future studies will investigate how early disease can be detected in these mice and will use genetic approaches to reconstitute the NKT cell compartment in these animals and assess the protective effects of normal NKT cell function on the progression of this disease.