B-cell chronic lymphocytic leukemia (B-CLL) represents a human neoplastic disorder which arises primarily because of failures in the normal mechanisms for the cell turnover through programmed cell death, rather than as a result of alterations in cell cycle regulation. Genetic alterations that inhibit normal programmed cell death can render tumor cells more resistant to apoptosis induction by anticancer drugs. Previous studies have documented abnormalities in the expression of certain Bcl-2 family proteins in B-CLLs. This family of proteins plays a critical role in controlling cellular responses to apoptotic stimuli, including those induced by essentially all chemotherapeutic drugs. The central hypothesis to be tested in this proposal is that alterations in the expression or function of apoptosis-regulatory proteins represents a critical obstacle to successfully treating B-CLL. Among the questions that will be addressed during the testing of this hypothesis are : (1) Can differences in the expression or phosphorylation states of Bcl-2-, IAP-, caspase-family proteins explain why some B-CLL patients exhibit complete responses (CR) to chemotherapy while other do not (NR; PR)?; (2) How do purine nucleosides used in the treatment of B-CLL affect the expression or function of these apoptosis-regualtory proteins, and do differences in these events account for variations in clinical responses? Moreover is there a functional connection between purine nucleosides and the pro-apoptotic, dATP-binding protein Apaf-1? (3) Can kinase modulatory drugs, cytokines, or retinoids be employed in vitro for modulating the expression or function of apoptosis regulatory proteins, thus rendering B-CLLs more sensitive to conventional chemotherapeutic drugs? The results of these investigations are anticipated to improve understanding of the relation between defective apoptosis mechanisms in B-CLL and responses to therapy, and thus may generate strategies for improving the treatment of B- CLL patients.
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