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

Lookup NU author(s): Professor Jaap van Laar, Dr Anja Krippner-Heidenreich



In the lymph node (LN) environment, chronic lymphocytic leukemia (CLL) cells display increased NF-kappa B 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-alpha (TNF alpha)-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 LN microenvironment and results in NF-kappa B activation and TNF alpha production. In this study, we investigated the response of CLL cells to smac-mimetics in the context of CD40 stimulation. We found that treatment with smac-mimetics results in cIAP1 and cIAP2 degradation, yet although TNF alpha is produced, this did not induce apoptosis. Despite the presence of all components, the ripoptosome complex did not form upon smac-mimetic treatment in CLL cells. Thus, CLL cells seem to possess aberrant upstream NF-kappa B regulation that prevents ripoptosome formation upon IAP degradation. Unraveling the exact molecular mechanisms of disturbed ripoptosome formation may offer novel targets for treatment in CLL.

Publication metadata

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

Publication type: Article

Publication status: Published

Journal: Cell Death and Disease

Year: 2013

Volume: 4

Online publication date: 29/08/2013

Acceptance date: 17/07/2013

Date deposited: 19/01/2015

ISSN (electronic): 2041-4889

Publisher: Nature Publishing Group


DOI: 10.1038/cddis.2013.305


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