title: Induction of autophagy-dependent   necroptosis is required for childhood   acute lymphoblastic leukemia cells   to overcome glucocorticoid resistance.
abstract: In vivo resistance to first-line chemotherapy, including to glucocorticoids, is a strong predictor of poor outcome in children with acute lymphoblastic leukemia (ALL). Modulation of cell death regulators represents an attractive strategy for subverting such drug resistance. Here we report complete resensitization of multidrug-resistant childhood ALL cells to glucocorticoids and other cytotoxic agents with subcytotoxic concentrations of obatoclax, a putative antagonist of BCL-2 family members. The reversal of glucocorticoid resistance occurred through rapid activation of autophagy-dependent necroptosis, which bypassed the block in mitochondrial apoptosis. This effect was associated with dissociation of the autophagy inducer beclin-1 from the antiapoptotic BCL-2 family member myeloid cell leukemia sequence 1 (MCL-1) and with a marked decrease in mammalian target of rapamycin (mTOR) activity. Consistent with a protective role for mTOR in glucocorticoid resistance in childhood ALL, combination of rapamycin with the glucocorticoid dexamethasone triggered autophagy-dependent cell death, with characteristic features of necroptosis. Execution of cell death, but not induction of autophagy, was strictly dependent on expression of receptor-interacting protein (RIP-1) kinase and cylindromatosis (turban tumor syndrome) (CYLD), two key regulators of necroptosis. Accordingly, both inhibition of RIP-1 and interference with CYLD restored glucocorticoid resistance completely. Together with evidence for a chemosensitizing activity of obatoclax in vivo, our data provide a compelling rationale for clinical translation of this pharmacological approach into treatments for patients with refractory ALL.
authors.affiliation: Department of Oncology, University Children's Hospital, University of Zurich, Switzerland.
authors.forename: Laura
authors.initials: L
authors.lastname: Bonapace
authors.forename: Beat C
authors.initials: BC
authors.lastname: Bornhauser
authors.forename: Maike
authors.initials: M
authors.lastname: Schmitz
authors.forename: Gunnar
authors.initials: G
authors.lastname: Cario
authors.forename: Urs
authors.initials: U
authors.lastname: Ziegler
authors.forename: Felix K
authors.initials: FK
authors.lastname: Niggli
authors.forename: Beat W
authors.initials: BW
authors.lastname: Schäfer
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bourquin
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000502:physiology; D001343:Autophagy; D000071186:Beclin-1; D003907:Dexamethasone / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D008565:Membrane Proteins / Q000737:chemistry / Q000502:physiology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D028861:Nuclear Pore Complex Proteins / Q000502:physiology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry; D011758:Pyrroles / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D023041:Xenograft Model Antitumor Assays
chemical_list: C119724:AGFG1 protein, human; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D005938:Glucocorticoids; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; C579095:MCL1 protein, human; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D028861:Nuclear Pore Complex Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D016601:RNA-Binding Proteins; D003907:Dexamethasone; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C520962:obatoclax