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Schmitt, Anja; Xu, Wendan; Bucher, Philip; Grimm, Melanie; Konantz, Martina; Horn, Heike; Zapukhlyak, Myroslav; Berning, Philipp; Brändle, Marc; Jarboui, Mohamed-Ali; Schönfeld, Caroline; Boldt, Karsten; Rosenwald, Andreas; Ott, German; Grau, Michael; Klener, Pavel; Vockova, Petra; Lengerke, Claudia; Lenz, Georg; Schulze-Osthoff, Klaus; Hailfinger, Stephan
Blood, 09/2021, Letnik: 138, Številka: 10Journal Article
Despite the development of novel targeted drugs, the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) still poses a substantial therapeutic challenge. DLBCL can be classified into at least 2 major subtypes (germinal center B cell GCB-like and activated B cell ABC-like DLBCL), each characterized by specific gene expression profiles and mutation patterns. Here we demonstrate a broad antitumor effect of dimethyl fumarate (DMF) on both DLBCL subtypes, which is mediated by the induction of ferroptosis, a form of cell death driven by the peroxidation of phospholipids. As a result of the high expression of arachidonate 5-lipoxygenase in concert with low glutathione and glutathione peroxidase 4 levels, DMF induces lipid peroxidation and thus ferroptosis, particularly in GCB DLBCL. In ABC DLBCL cells, which are addicted to NF-κB and STAT3 survival signaling, DMF treatment efficiently inhibits the activity of the IKK complex and Janus kinases. Interestingly, the BCL-2–specific BH3 mimetic ABT-199 and an inhibitor of ferroptosis suppressor protein 1 synergize with DMF in inducing cell death in DLBCL. Collectively, our findings identify the clinically approved drug DMF as a promising novel therapeutic option in the treatment of both GCB and ABC DLBCLs. •As a result of low glutathione and glutathione peroxidase 4 levels and high 5-lipoxygenase expression, DMF induces ferroptosis in GCB DLBCL.•In ABC DLBCL, DMF induces succination of kinases IKK2 and JAK1, thus inhibiting NF-κB and JAK/STAT survival signaling. Display omitted
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in: SICRIS
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