title: The E3 ubiquitin ligase TRAF2 can contribute to TNF-α resistance in FLT3-ITD-positive AML cells.
abstract: TNF-α has pleiotropic effects on cell survival and apoptosis. The E3 ubiquitin ligase TRAF2 plays a crucial role for TNF-α mediated signaling since NF-κB activation by TNF-α is at least partially mediated by TRAF2. The objective of this study was to investigate whether TNF-α can induce apoptosis in FLT3-ITD-positive AML cells and to elucidate the influence of TRAF2. Stable lentiviral mediated down-regulation of TRAF2 resulted in a decrease of phosphorylation of the anti-apoptotic protein AKT and its downstream target GSK-3β. Induction of apoptosis and impaired proliferation after TNF-α exposure were observed. Co-treatment of FLT3-ITD-positive cells with the specific FLT3 inhibitor AC220 was able to overcome TNF-α resistance. Taken together, we conclude that TRAF2 plays an important role in signal transduction and survival of AML cells.
authors.affiliation: Abteilung Hämatologie/Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Schnetzke
authors.forename: Mike
authors.initials: M
authors.lastname: Fischer
authors.forename: Bärbel
authors.initials: B
authors.lastname: Spies-Weisshart
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Zirm
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Jörg P
authors.initials: JP
authors.lastname: Müller
authors.forename: Sebastian
authors.initials: S
authors.lastname: Scholl
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020080:Tandem Repeat Sequences; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
keywords: AC220; AML; FLT3-ITD; TNF-α; TRAF2