The long-term objective of this project is to understand whether B cell tumors can arise by receptor-mediated tumorigenesis. Such a model was proposed by McGrath and Weissman to explain how lymphoid tumors could arise in mice following continuous stimulation of cells by endogenous antigens which might be of bacterial or viral origin. We have found that the CD5+ B cell tumor line, NYC, that was isolated from a (NZBxNZW)F1 mouse, secretes retroviral particles. These particles can be co- precipitated with the tumor cell immunoglobulin (Ig), suggesting that the Ig receptors of NYC cells may react with the viral particles. Furthermore, the VH region expressed by NYC cells is identical to VH regions expressed by leukemic CD5 + B cells in old (NZBxNZW)F1 mice and by two non-related CD5+ B cell tumors from NZB mice. This suggests that these tumors may have arisen by stimulation of B cells having the same antigen receptor as is expressed by the NYC tumor, i.e. CD5+ B cell tumors in (NZBxNZW)F1 and NZB mice develop by receptor-mediated tumorigenesis. We hypothesize that this may be a common mechanism for the generation of B cell tumors. The first goal of this proposal is to determine if we can find other examples of CD5+ B cell tumors that could have been generated by such a receptor-mediated mechanism. Therefore, we will test established CD5+ B cell tumor lines for the presence of molecules that co-precipitate with tumor cell Ig. In addition, we will generate and characterize other CD5 + B cell tumor lines from NZB and (NZBxNZW)F1 mice since it has been shown that these mice synthesize mature endogenous viral particles and develop monoclonal B cell tumors that preferentially express one particular VH region. Another set of experiments will test in NYC cells three predictions that arise from the receptor-mediated tumorigenesis model. One of these predictions is that the growth of NYC cells should depend upon the presence of surface Ig receptors. We also plan to extend our search for endogenous antigens to human leukemic CD5+ B cells isolated from patients with chronic lymphocytic leukemia (CLL) since 30% of unrelated B- CLL tumors express the same VH region. Finally, we will use anti-epitope antibodies to search for endogenous antigens in human and mouse tissues. This proposed study will contribute to the understanding of how the continuous expression of an endogenous antigen can lead to the formation of B cell tumors.
