The long-term goal of this project remains an understanding of the mechanisms that promote transformation and progression of B cell lymphomas. To this end, we have focused, and will continue to focus on avian Lymphoid Leukosis (LL) as a model system. Like other lymphomagenic systems, the natural history of LL has been characterized as a multistage process of transformation that involves pre-neoplastic, neoplastic and metastaic stages; however the basis for progression from one stage to the next is poorly understood. We will take advantage of expertise recently developed in our laboratory to isolate individual hyperplastic follicles that will now permit analysis of cells at all three stages of LL tumor development. We propose to analyze factors intrinsic to the B cell that are likely to be integral to the transformation process, i.e., provival composition, orientation and site of integration, and single or multiple proto-oncogene activation, to determine their role in the transformation and progression of the LL tumors. We will also examine the relationship between the state of cellular differentiation/maturation, and the susceptibility of B cells to transformation and the potential of transformed B cells to metastasize. Finally, we will analyse the effects of the selective pressures caused by immune mechanisms on the progression of cells at each stage of lymphomagenesis. These experiments should provide insight into the mechanisms of neoplastic transformation and tumor progression as well as the processes of normal B cell development and thereby a context for the interpretation of the neoplastic changes.