B cell lymphoma is a major class of spontaneous malignant disease, and its occurence is strongly correlated with increasing age, genetic background, and certain acquire immunodeficient states. In the previous grant period, we characterized the pattern of I expression and growth control in long-term Ly-1+ B cell lines (B-Ly1 cells). In particular, we noted that these cells displayed neoplastic growth properties in vitro and various degrees of tumorigenicity in vivo' despite their original derivation from normal mice. B-Ly1 cell lines thus appear to offer a new in vitro lymphomagenesis model to recover and study neoplastic B cells at early stages of malignant progression. In the rew grant period, we use this model to test the hypothesis that the initial stages of B cell lymphomagenesis represent an aberrant but potentially reversible differentiative state.
Our specific aims address these questions: What are the recipient host mechanisms which suppress tumorigenicity B-Ly1 cells? The host cell types and cytokines which suppress tumorigenicity and in vitro B-Ly1 cell growth will be defined. We will also determine whether the mechanism is cytotoxic, or it instead involves differentiation of B-Ly1 cells into a non-tumorigenic state. What subpopulation serves as the precursor for B-Ly1 cell lines? Using a quantitative in vitro outgrowth assay, we will characterize the phenotype of the in vivo precursor cell according to pattern of surface differentiatior antigens and Ig variable region and isotype expression. In addition, we will directly monitor the in vivo properties of a representative Ly-1+ B cell population expressing a characteristic VH gene family recently cloned in our laboratory. Which of these host and precursor parameters account for the elevated occurrence of lymphoma in the aged individual, and as a consequence of certain genetic or acquired traits? We will assess whether experimentally-defined mechanisms permissive for B-Ly1 neoplastic growth correlate with murine animal models exemplifying natural lymphomagenic processes.
