title: Targeting inhibitor of apoptosis proteins by Smac mimetic elicits cell death in poor prognostic subgroups of chronic lymphocytic leukemia.
abstract: Inhibitor of apoptosis (IAP) proteins are highly expressed in chronic lymphocytic leukemia (CLL) cells and contribute to evasion of cell death and poor therapeutic response. Here, we report that Smac mimetic BV6 dose-dependently induces cell death in 28 of 51 (54%) investigated CLL samples, while B-cells from healthy donors are largely unaffected. Importantly, BV6 is significantly more effective in prognostic unfavorable cases with, e.g., non-mutated VH status and TP53 mutation than samples with unknown or favorable prognosis. The majority of cases with 17p deletion (10/12) and Fludarabine refractory cases respond to BV6, indicating that BV6 acts independently of p53. BV6 also triggers cell death under survival conditions mimicking the microenvironment, e.g., by adding CD40 ligand or conditioned medium. Gene expression profiling identifies cell death, NF-κB and redox signaling among the top pathways regulated by BV6 not only in CLL but also in core-binding factor (CBF) acute myeloid leukemia (AML). Consistently, BV6 stimulates production of reactive oxygen species (ROS), which are contributing to BV6-induced cell death, since antioxidants reduce cell death. While BV6 causes degradation of cellular inhibitor of apoptosis (cIAP)1 and cIAP2 and nuclear factor-kappaB (NF-κB) pathway activation in primary CLL samples, BV6 induces cell death independently of caspase activity, receptor-interacting protein (RIP)1 activity or tumor necrosis factor (TNF)α, as zVAD.fmk, necrostatin-1 or TNFα-blocking antibody Enbrel fail to inhibit cell death. Together, these novel insights into BV6-regulated cell death in CLL have important implications for developing new therapeutic strategies to overcome cell death resistance especially in poor prognostic CLL subgroups.
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Opel
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schnaiter
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Dodier
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: Marjana
authors.initials: M
authors.lastname: Jovanovic
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Gerhardinger
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Idler
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mertens
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics, , Goethe University, Frankfurt, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Fulda
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors*; D016923:Cell Death / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D018716:Molecular Mimicry; D016328:NF-kappa B / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D011379:Prognosis; D059748:Proteolysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C582180:BV6 peptide; D016328:NF-kappa B; D009842:Oligopeptides; D017382:Reactive Oxygen Species; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha
keywords: CLL; IAP proteins; Smac mimetic; cell death