Retrovirally-induced Leukemias in MiceF-MuLV Infection of gp91-phox Transgenic Mice: A Model for Myelomonocytic LeukemiaThe mouse represents a premier model for the study of cancer and the identification of genes involved in cancer. Some of the earliest studies on the mouse were aimed at the development of strains with high incidence of cancer, particularly in the hematopoietic system and in the mammary gland. In several of the strains that were developed, such as AKR, which is susceptible to thymic lymphomas, and C3H, which develop mammary tumors, the tumorigenesis is a result of retroviral infection. As part of the retroviral life cycle, a DNA copy of the virus (termed a provirus) inserts into the genomic DNA of the infected somatic cell, in what appears to be a fairly random manner in terms of the site of insertion. This insertion event can result in the alteration of the structure and function of the genes in the region around the insertion, leading to either increased expression, of the normal protein product(s) or, in some cases, production of truncated protein products. If the gene into which the provirus inserts is involved in the regulation of cell growth, then that insertion event can give that cell a selective growth advantage, and this can constitute a step in the progression towards cancer. A key step in understanding the cancer process is to identify the contributory genes and to determine what proteins they encode, and how these work to deregulate cellular growth. In retrovirally-induced cancers, the genes that are sites of proviral insertion can be readily identified by isolation of the DNA near the insertion site by PCR, and sequence analysis. Since the sequence of the mouse genome is available now, it is very straightforward to identify the genes in the region around the proviral insertion. When genes are repeatedly identified as insertion sites, in more than one tumor, they are considered “common” sites of proviral insertion, and likely contribute to the cancer process. A database of such insertion sites from hematopoietic tumors has been established by Neal Copeland and colleagues. We are interested in genes involved in the development of tumors of the myelomonocytic lineage, and have created a mouse model in which these occur at high frequency, due to the combined effect of a oncogenic transgene (gp91phox-SV40 T antigen) and the Friend murine leukemia virus (F-MuLV). We have recently described this model in the downloadable publication. While F-MuLV can induce erythroleukemias, in the strain we are using (C57BL6 mice) it induces myeloid leukemias and B cell lymphomas. We have infected a cohort of gp91phox-T antigen transgenic mice as neonates with F-MuLV, which resulted in a high incidence of myelomonocytic tumors. Using inverse PCR, we have been able to clone out numerous insertion sites in these tumors, many of which are novel to this model. These insertions serve as a starting point for the dissection of the pathways involved in the development of myelomonocytic tumors in this strain of mouse. Publications |
 |
