Abstract
Dysfunctional apoptotic machinery is a hallmark feature of chronic lymphocytic leukemia (CLL). Accordingly, targeting apoptosis regulators has been proven a rational approach for CLL treatment. We show that CLL lymphocytes express high levels of XIAP, cIAP1, and cIAP2 compared to normal lymphocytes. Smac mimetic, Smac066, designed to bind to BIR3-domain of IAPs, induce apoptosis in primary CLL cells (n=71; p<0.0001), irrespective of prognostic markers. Apoptosis was mediated by diminished levels of IAPs (XIAP-p=0.02; cIAP-p<0.0001) and increased activation of caspases-8, −9, −3. The caspase-cleavage was in direct association with the levels of apoptosis (r2=0.8 for caspases-8, −9, −3). Correlative analysis revealed a direct relationship between reduction in IAPs and degree of apoptosis (r2=0.6 (XIAP); 0.5 (cIAP2)). There was a strong association between apoptosis, IAP-degradation, and concurrent caspase-activation. Pan-caspase inhibitor Z-Vad-fmk reversed the degradation of Mcl-1, but not IAPs suggesting that smac066 is selective to IAPs, however, Mcl-1 degradation is through caspase-mediated cleavage. Immunoprecipitation experiments revealed physical interaction between caspase-3 and XIAP that was disrupted by smac066. Importantly, XIAP and cIAP2 were markedly induced in bone-marrow and lymph-node microenvironments, providing a basis for IAP antagonists as anti-tumor agents in CLL. Smac066 synergized with ABT-737, revealing a mechanistic rationale to jointly target BH3 and BIR3 domains.
Highlights
Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the Western world
We show that chronic lymphocytic leukemia (CLL) lymphocytes express high levels of X-linked IAP (XIAP), cellular IAP1 (cIAP1), and cIAP2 compared to normal lymphocytes
There was a strong association between apoptosis, inhibitorof-apoptosis proteins (IAPs)-degradation, and concurrent caspase-activation
Summary
Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the Western world. Smac066, designed to bind to BIR3-domain of IAPs, induce apoptosis in primary CLL cells (n=71; p
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