In this grant a murine model of lymphoproliferation will be analyzed to determine the molecular events involved in the clonal expansion of B-1 cells. The NZB strain develops clones of B-1 cells and is a model of chronic lymphocytic leukemia (CLL). Three different types of B-1 expanded populations will be studied: (1) pre-CLL in which the B-1 cells are expanded and several slow growing clones may be present, these appear in normal and (NZB, X DBA /2)Fl mice as late-appearing clones (2) CLL-like in which clonal expansion occurs and hyperdiploid B-1 clones develop which are non-aggressive, and (3) the expression of an aggressive invasive neoplasia of B-1 cells similar to that seen in Richter's. These three separate types of B-1 cells will be examined for both shared and unique characteristics which may be responsible for the clonal expansion. The B-1 clones will be analyzed for the ability to undergo apoptosis, a feature of fetal pre-B cells and a possible mechanism for the deletion of self-reactive cells and cells incapable of responding to a specific antigen. The possibility that apoptosis is increased in the early appearing B-1 hyperdiploid clones which develop into aggressive neoplasias and absent from the late appearing slow-growing clones may allow the possible use of apoptosis induction in the regulation of the growth of these neoplasias. The immunoglobulin sequence of the B-1 clones both early and late appearing will be studied. It is hypothesized that the neoplastic clones are similar to fetal B cells in the CDR3 region with very little N base substitutions. Molecular modeling studies will help to determine if developmental restrictions in the CDR3 region result in a unique binding site for the early appearing B-1 clones. Other characteristics of fetal B cells will be studied in the B-1 clones such as lambda 5 gene expression and cytokine expression. The role of IL-10 levels in both the development of B-1 neoplasias and the induction of apoptosis will be studied. Preliminary results have indicated that NZB mice that live nearly twice as long as the average life-span do not develop hyperdiploid B-1 malignancies but rather display T cell expansions. The cytokine profiles of these T cell clones will be studied as well as in vivo transfers of these T cells to determine the possible therapeutic role of T cells in the prevention of B-1 neoplasias. Finally, the genes responsible for the development of hyperdiploid B-1 clones will be investigated at a molecular level by two different techniques. The first technique will look for genetic polymorphisms in F2 and backcross animals which are linked to the expression of hyperdiploid B-1 clones. Another technique will use an mRNA subtraction library made up of the differences between slow and fast growing B-1 malignancies. The ultimate goal is to identify in the lymphoproliferative condition the genes responsible for the uncontrolled clonal expansion of B-1 neoplasias.
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