title: Smac mimetic and glucocorticoids synergize to induce apoptosis in childhood ALL by promoting ripoptosome assembly.
abstract: Apoptosis resistance contributes to poor outcome in pediatric acute lymphoblastic leukemia (ALL). Here, we identify a novel synergistic combination of Smac mimetic BV6 and glucocorticoids (GCs) (ie, dexamethasone, prednisolone) to trigger apoptosis in ALL cells. BV6 and GCs similarly cooperate to induce apoptosis in patient-derived leukemia samples, underlining the clinical relevance. Importantly, BV6/dexamethasone cotreatment is significantly more effective than monotherapy to delay leukemia growth in a patient-derived xenograft model of pediatric ALL without causing additional side effects. In contrast, BV6 does not increase cytotoxicity of dexamethasone against nonmalignant peripheral blood lymphocytes, mesenchymal stromal cells, and CD34-positive hematopoietic cells. We identify a novel mechanism by showing that BV6 and dexamethasone cooperate to deplete cIAP1, cIAP2, and XIAP, thereby promoting assembly of the ripoptosome, a RIP1/FADD/caspase-8-containing complex. This complex is critical and is required for BV6/dexamethasone-induced cell death, because RIP1 knockdown reduces caspase activation, reactive oxygen species production, and cell death. Ripoptosome formation occurs independently of autocrine/paracrine loops of death receptor ligands, because blocking antibodies for TNFα, tumor necrosis factor-related apoptosis-inducing ligand, or CD95 ligand or knockdown of death receptors fail to rescue BV6/dexamethasone-induced cell death. This is the first report showing that BV6 sensitizes for GC-triggered cell death by promoting ripoptosome formation with important implications for apoptosis-targeted therapies of ALL.
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics.
authors.forename: Katharina
authors.initials: K
authors.lastname: Belz
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics.
authors.forename: Hannah
authors.initials: H
authors.lastname: Schoeneberger
authors.affiliation: Pediatric Hematology and Oncology, Children's Hospital.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Wehner
authors.affiliation: Institute of Biochemistry I, and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Weigert
authors.affiliation: Institute for Transfusion Medicine and Immunohematology, Goethe-University, Frankfurt, Germany; and.
authors.forename: Halvard
authors.initials: H
authors.lastname: Bönig
authors.affiliation: Pediatric Hematology and Oncology, Children's Hospital.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klingebiel
authors.affiliation: Experimental Pharmacology, Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany.
authors.forename: Iduna
authors.initials: I
authors.lastname: Fichtner
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics.
authors.forename: Simone
authors.initials: S
authors.lastname: Fulda
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D004357:Drug Synergism; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology*; D055503:Protein Multimerization / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: C582180:BV6 peptide; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D020690:GTPase-Activating Proteins; D005938:Glucocorticoids; D009842:Oligopeptides; C490620:Ralbp1 protein, mouse; D053181:Caspase 8