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Smac mimetic and glucocorticoids synergize to induce apoptosis in childhood ALL by promoting ripoptosome assembly

Official URL:https://doi.org/10.1182/blood-2013-05-500918
PubMed:View item in PubMed
Creators Name:Belz, K. and Schoeneberger, H. and Wehner, S. and Weigert, A. and Boenig, H. and Klingebiel, T. and Fichtner, I. and Fulda, S.
Journal Title:Blood
Journal Abbreviation:Blood
Volume:124
Number:2
Page Range:240-250
Date:10 July 2014
Keywords:Apoptosis, Caspase 8, Cultured Cells, Drug Synergism, Fas-Associated Death Domain Protein, GTPase-Activating Proteins, Glucocorticoids, Inbred NOD Mice, Oligopeptides, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Protein Multimerization, SCID Mice, Transgenic Mice, Xenograft Model Antitumor Assays, Animals, Mice
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.
ISSN:0006-4971
Publisher:American Society of Hematology (U.S.A.)
Item Type:Article

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