B-cell chronic lymphocytic leukemia (B-CLL), the most common non-solid tumor in western societies, currently has no effective treatment. Conventional chemotherapeutic drugs are toxic and not well suited to the biology of the disease. In studies that have begun to elucidate the structural requirements of the induction of in vivo targeted death of primary B lymphocytes, we have shown that the bacterial toxin, Staphylococcus aureus protein A (SPA) forms complexes with membrane B-cell receptors (BCR) that induce programmed cell death. The current studies will characterize the properties of the pro-apoptotic BCR complex, and assess whether co-blocking of other immunological survival signals can enhance this potential therapeutic approach.
SPECIFIC AIMS : These studies will evaluate basic mechanisms, and consider the overall relevance and efficacy of treatment in an in vivo model of human B-CLL deletion.
Aim 1 : To define the nature of the pro-apoptotic ligand-BCR complexes on healthy and leukemic Human B cells. Studies will be carried out to reveal the SpA-BCR complexes formed on healthy and CLL B-cells. Using flow cytometry and de-convoluted con-focal microscopy, we will characterize the pro-apoptotic complexes, and specific constituents required to cause activation and signaling of these B-cells in vitro.
Aim 2 : To evaluate the sensitivity of B-CLL cells to BCR-induced deletion in an in vivo RAG -/- transfer model. We will investigate the deletion of transferred healthy and CLL B-cells in RAG-1 -/- mice and evaluate whether the specific B-CLL subset can be deleted with SpA (VH3-specific) and also investigate the mechanism(s) associated with B-cell deletion.
Aim 3 : To evaluate the enhancement of BCR induced apoptosis in B cells by simultaneously blocking alternative immunological survival signals. To further define how BCR targeting can be utilized as a therapeutic reagent, different pathways of activation-induced cell death will be considered and how they can be enhanced by the addition of various inhibitors for immunological survival signals i.e., TACI-Fc or anti- BAFF antibodies.
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