title: CLL cells are resistant to smac mimetics because of an inability to form a ripoptosome complex.
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 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.
authors.affiliation: Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Maas
authors.forename: J M
authors.initials: JM
authors.lastname: Tromp
authors.forename: J
authors.initials: J
authors.lastname: van Laar
authors.forename: R
authors.initials: R
authors.lastname: Thijssen
authors.forename: J A
authors.initials: JA
authors.lastname: Elias
authors.forename: A
authors.initials: A
authors.lastname: Malara
authors.forename: A
authors.initials: A
authors.lastname: Krippner-Heidenreich
authors.forename: J
authors.identifier: 0000000276115774
authors.initials: J
authors.lastname: Silke
authors.forename: M Hj
authors.initials: MH
authors.lastname: van Oers
authors.forename: E
authors.initials: E
authors.lastname: Eldering
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D001713:Biphenyl Compounds / Q000494:pharmacology; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000473:pathology*; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D044767:Ubiquitin-Protein Ligases
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D019013:CD40 Antigens; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D016328:NF-kappa B; D009596:Nitrophenols; D010879:Piperazines; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; C494833:BIRC2 protein, human; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex