The ability of retroviruses to induce an increased incidence of neoplasia has been documented in a variety of species. The most recent example is the increased incidence of cancer in patients infected with HIV. For the last 10 years, our laboratory has focused on defining the mechanisms by which avian retroviruses induce B cell transformation during development in the bursa of Fabricius. When chickens are infected in the perinatal period with avian leukosis (ALV), a retrovirus that does not contain a known transforming segment, 50-70% of birds in susceptible strains develop B cell lymphomas by 5-6 months of age. The development of these tumors is dependent upon the bursa of Fabricius. Up until one month after infection the risk of lymphoma can be completely eliminated by bursectomy of the animals. One gene that plays a fundamental role in the pathogenesis of these tumors has been identified. In over 90% of bursal lymphomas, ALV integration has occurred within the c-myc gene locus. However, dysregulation of myc gene expression is not sufficient to account for the neoplastic phenotype since avian retroviruses containing a myc oncogene cannot directly induce B cell neoplasia, but instead lead to the development of an intermediate lesion known as a transformed follicle. Transformed follicle cells are proliferating lymphomas whose survival is dependent on the bursal environment, and these cells become susceptible to secondary transforming events that lead to neoplastic progression. One potential mechanism for genetic instability in these cells results from the fact that the cells are constitutively undergoing gene conversion of their immunoglobulin gene loci. Immunoglobulin gene conversion is a normal developmental process that is used to generate diversity within the rearranged immunoglobulin genes of avian species. However, gene conversion provides a potential mechanism for acquisition of additional genetic alterations in myc-transformed cells. One cardinal feature of a bursal lymphocyte that has undergone neoplastic progression is its loss of dependence on the bursal environment for survival. The apparent mechanism for this feature of neoplastic progression is a loss of susceptibility to programmed cell death (apoptosis) that occurs when normal bursal lymphocytes are separated from the bursal environment. So far, we have cloned one gene, bcl-x, which appears to regulate the susceptibility of bursal cells to apoptotic cell death during development. The role of bcl-x in ALV-induced lymphomagenesis will be investigated. Because the site of B cell development is well defined in avian species, the bursa of Fabricius provides an important model system for studying cellular differentiation and transformation in vertebrates.
The specific aims of our proposal are to: (i) develop a clear molecular description of the stages of avian B cell development within the bursa of Fabricius; (ii) define the mechanism by which immunoglobulin gene conversion occurs and its potential role in the generation of genetic instability during B cell development; and (iii) determine the molecular mechanisms that regulate programmed cell death during B cell development.
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