Lymphoid and mesenchymal tumors in transgenic mice expressing the v-fps protein-tyrosine kinase
1Division of Molecular and Developmental Biology, Mt. Sinai Hospital Research Institute, Toronto, Ontario, Canada.
Abstract:
src, abl, and fps/fes are prototypes for a family of genes encoding nonreceptor protein-tyrosine kinases. The oncogenic potential of the v-fps protein-tyrosine kinase was investigated by introduction of the gag-fps coding sequence of Fujinami sarcoma virus into the mouse germ line. Transgenic mice with v-fps under the transcriptional control of a 5' human beta-globin promoter (GF) or with both 5' and 3' beta-globin regulatory sequences (GEF) were viable. Unexpectedly, both GF and GEF transgenes were expressed in a wide variety of tissues and induced a spectrum of benign and malignant tumors. These tumors, which included lymphomas, thymomas, fibrosarcomas, angiosarcomas, hemangiomas, and neurofibrosarcomas, developed with various frequencies after latent periods of 2 to 12 months. The majority of lymphoid neoplasms appeared to be of T-cell origin and were monoclonal, as judged by rearrangements of the T-cell receptor beta or immunoglobulin genes. Some tissues that expressed the v-fps oncogene, such as heart, brain, lung, and testes, developed no malignant tumors. The v-fps protein-tyrosine kinase therefore has a broad but not unrestricted range of oncogenic activity in cells of lymphoid and mesenchymal origin. The incomplete penetrance of the neoplastic phenotype and the monoclonality of lymphoid tumors suggest that tumor formation in v-fps mice requires genetic or epigenetic events in addition to expression of the P130gag-fps protein-tyrosine kinase.
Insights
The v-fps oncogene, when introduced into mice, triggered diverse benign and malignant tumors, primarily in lymphoid and mesenchymal tissues. Tumor development indicates additional genetic factors are needed beyond v-fps expression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Nonreceptor protein-tyrosine kinases, including src, abl, and fps/fes, are crucial in cellular signaling.
- The v-fps oncogene, derived from Fujinami sarcoma virus, is a potent protein-tyrosine kinase with oncogenic potential.
Purpose of the Study:
- To investigate the oncogenic potential of the v-fps protein-tyrosine kinase in vivo.
- To determine the spectrum of tumors induced by germ line transmission of the v-fps oncogene in mice.
Main Methods:
- Generation of transgenic mice harboring the gag-fps coding sequence under the control of beta-globin regulatory elements (GF and GEF models).
- Analysis of transgene expression patterns across various tissues.
- Histopathological examination and molecular characterization (T-cell receptor and immunoglobulin gene rearrangements) of induced tumors.
Main Results:
- Transgenic mice expressing v-fps developed a wide range of benign and malignant tumors, including lymphomas, thymomas, and various sarcomas.
- Tumorigenesis occurred with varying frequencies and latent periods (2-12 months) across different tissues.
- Lymphoid neoplasms were predominantly of T-cell origin and monoclonal, indicating specific cellular targets and clonal expansion.
- Certain tissues (heart, brain, lung, testes) expressing v-fps did not develop tumors, suggesting tissue-specific susceptibility.
Conclusions:
- The v-fps protein-tyrosine kinase exhibits broad oncogenic activity in lymphoid and mesenchymal cells.
- Tumor formation in v-fps transgenic mice is not fully penetrant, implying that additional genetic or epigenetic events are required.
- The monoclonality of lymphoid tumors highlights the complex interplay between oncogene expression and host factors in neoplastic development.
