Based on the criterion of restricted surface membrane Ig (SIg) expression non-Hodgkin's lymphomas represent expansions of single clones of B cells. This definition of clonality is clearly inadequate in many instances since SIg is either not present at all or not clearly restricted. Since our concepts of clonal origin are imprecise, even less is known about clonal evolution, particularly with respect to clonal stability and clonal transformation. Based on preliminary data we hypothesize that: 1. multiclonality is a more common event than was formerly realized; 2. genetic polymorphisms may be useful as an index of clonal instability and, 3. certain events related to the expression of cell surface differentiation antigens and Ig idiotype may signal clonal transformation. We will bring more powerful definitions of clonality to study these issues. We will examine DNA harvested from these tumors for Ig gene rearrangements and gene polymorphisms using unique probes for restriction fragment length polymorphisms (RFLP) as well as prepare monoclonal anti-idiotypic antibodies from cell bound Ig or circulating idiotype. With these probes we will study SIg+ tumors, SIg- tumor and prelymphomatous states. Multiclonal origin will be investigated by analysis of cell populations based on idiotype expression or potentially discriminating clonotypic characteristics (monomorphic class II determinants and FcMuR receptor expression) that we have developed in our preliminary data. Likely candidates for multiclonality will be further studied by sorting cell populations and observing the segregation of Ig gene rearrangements to a given cell population. An analysis of the expression of gene polymorphisms will provide information relevant to clonal instability. In certain cases serum idiotype measurements and phenotypic criteria will be correlated with transformation to a more aggressive biologic behavior. These data will be crucial in developing a model of human lymphoma that correlates molecular genetic events at the clonal level with surface membrane phenotype and histomorphology. The ultimate importance of these studies is to utilize this model in: 1. immunodiagnosis; 2. the development of a set of criteria that will be more useful and broadly applicable in predicitng prognosis; 3. the design of more effective treatment strategies, particularly those based on specifically targeted molecules such as monoclonal antibodies or anti-idiotypic antibodies.
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