Biochemistry of Apoptosis in CLL

University Of California, San Diego, La Jolla CA

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Abstract

B-cell chronic lymphocytic leukemia [B-CLL] is a human neoplastic disorder characterized by the progressive[unreadable] accumulation of quiescent B lymphocyte. We have hypothesized that B CLL arises primarily because of[unreadable] failures in the normal mechanisms of cell turnover through programmed cell death, rather than as a result of[unreadable] alterations in cell cycle regulation, and that anomalies in the expression and function of apoptosis-regulatory[unreadable] proteins are the critical obstacle to the successful treatment of this malignancy. The overall goal of the[unreadable] biochemistry component of the B-CLL Research Consortium [CRC] is to define the fundamental[unreadable] abnormalities of apoptosis regulation in B-CLL, and to devise targeted treatments that address the basic[unreadable] problems. During the previous funding period, our experiments have demonstrated that several pro-apoptotic[unreadable] proteins [including Bax, BH3-only proteins such as Bim, caspases] are abundantly expressed in B-CLL but[unreadable] are maintained in an inactive state by the concomitant high-level expression of specific anti-apoptotic[unreadable] proteins [including Bcl-2, Mcl-1, lAPs, FLIP]. Accordingly, the specific hypothesis to be tested in this renewal[unreadable] application is that chemical agents that release pro-apoptotic proteins from inhibitory complexes will trigger[unreadable] apoptosis of B-CLL cells, or render these malignant cells more susceptible to cytotoxic therapy or[unreadable] immunotherapy. Working in collaboration with members of the CRC and other scientists, we have identified[unreadable] several new agents that can overcome in vitro some of the apoptosis defects in B-CLL. These prototype[unreadable] compounds have been demonstrated to block Bcl-2 interaction with BH3 proteins, to reverse IAP inhibition of[unreadable] caspases, or to release the BH3-only protein Bim from microtubules. The focus of the planned experiments[unreadable] in the CRC grant renewal is to continue our preclinical analysis of these prototype therapeutics, testing their[unreadable] efficacy against cultured CLL B-cells, improving our understanding of their mechanisms of action, and[unreadable] optimizing approaches for employing these agents, in hope of rapidly bringing these concepts and the new[unreadable] agents into the clinic.