Chronic lymphocytic leukemia (CLL) cells circulating in peripheral blood (PB) differ from the leukemic fraction in lymph nodes (LNs) with respect to cell division and drug sensitivity. CD40 stimulation of PB CLL cells in vitro results in chemoresistance and provides a partial model for the LN microenvironment. The TLR9 ligand CpG induces proliferation in immunoglobulin variable heavychain-unmutated CLL, but apoptosis in immunoglobulin variable heavy-chain-mutated CLL. To juxtapose proliferative with antiapoptotic signals, we investigated the effects of CpG in the context of CD40 ligation in mutated versus unmutated CLL cells in this study. Prolonged CD40 ligation induced classical, followed by alternative nuclear factor-jB (NF-jB), activity in both subgroups, correlating with enhanced Bfl-1 and Bcl-X L levels, respectively. A dichotomy in NF-jB signaling occurred on combined CD40/TLR9 triggering. This induced declining p52 and Bcl-X L levels, and reversed chemoresistance only in mutated cells, whereas unmutated cells proliferated, maintained p52 and Bcl-X L and remained chemoresistant. The pivotal contribution of Bcl-X L to chemoresistance was shown by the BH3 mimetic ABT-737 and RNA interference. Finally, in ex vivo LN samples, p52, p65 and Bcl-X L levels were highly expressed, corroborating the in vitro findings. Thus, a distinction in NF-jB activation and drug susceptibility in mutated versus unmutated (LN-like) CLL cells was uncovered, which was causally linked to Bcl-X L levels.
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 LN microenvironment and results in NF-κB activation and TNFα 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 TNFα 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-κB 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.
Viral infections have more severe consequences in patients that have been exposed to cigarette smoke (CS). However, the mechanisms that underlie the exaggerated virus−induced responses in patients with COPD and CS−exposed individuals have not been adequately addressed. We recently demonstrated that CS selectively enhances the pulmonary inflammation, alveolar remodeling and apoptosis induced by the viral innate immune agonist (poly(I:C)) or influenza virus infection (ATS 2008). We hypothesized that CS−induced alterations in the RIG−I like RNA helicases (RLHs) antiviral innate immune pathway play a critical role in the pathogenesis of the tissue alterations induced by CS plus poly(I:C). We compared the pulmonary inflammation, apoptosis and remodeling responses induced by CS plus poly(I:C) in wild type (WT) and MAVS null (−/−) mice. Without MAVS, a mitochondrial adapter protein linking viral recognition by RLHs to downstream NF−κB activation and type I interferon (IFN) production, the exaggerated pulmonary inflammation and apoptosis induced by CS+poly(I:C) was significantly diminished. In addition, emphysematous lung destruction was also significantly ameliorated. This interaction was associated with the MAVS−dependent early induction of type I IFN, the later induction of IFN−γ and the activation of double−stranded RNA−dependent protein kinase (PKR). These studies demonstrate that CS−induced alterations in RLHs pathway activity may play a critical role in the pathogenesis of COPD and other CS and virus−associated lung pathologies. They also link, for the first time, the RLHs and PKR innate antiviral pathways. This abstract is funded by: HL−079328, HL−084225. Am J Respir Crit Care Med 179;2009:A4264 Internet address: www.atsjournals.org Online Abstracts Issue
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