Journal article

CLL cells are resistant to smac mimetics because of an inability to form a ripoptosome complex

C Maas, JM Tromp, J van Laar, R Thijssen, JA Elias, A Malara, A Krippner-Heidenreich, J Silke, MHJ van Oers, E Eldering

CELL DEATH & DISEASE | NATURE PUBLISHING GROUP | Published : 2013

Abstract

In the lymph node (LN) environment, chronic lymphocytic leukemia (CLL) cells display increased NF-κB activity compared with peripheral blood CLL cells, which contributes to chemoresistance. Antagonists of cellular inhibitor of apoptosis proteins (cIAPs) can induce apoptosis in various cancer cells in a tumor necrosis factor-α (TNFα)-dependent manner and are in preclinical development. Smac-mimetics promote degradation of cIAP1 and cIAP2, which results in TNFR-mediated apoptosis via formation of a ripoptosome complex, comprising RIPK1, Fas-associated protein with death domain, FLICE-like inhibitory protein and caspase-8. CD40 stimulation of CLL cells in vitro is used as a model to mimic the L..

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University of Melbourne Researchers