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Dimethyl fumarate induces ferroptosis and impairs NF-κB/STAT3 signaling in DLBCL

A. Schmitt, W. Xu, P. Bucher, M. Grimm, M. Konantz, H. Horn, M. Zapukhlyak, P. Berning, M. Brändle, MA. Jarboui, C. Schönfeld, K. Boldt, A. Rosenwald, G. Ott, M. Grau, P. Klener, P. Vockova, C. Lengerke, G. Lenz, K. Schulze-Osthoff, S. Hailfinger

. 2021 ; 138 (10) : 871-884. [pub] 20210909

Language English Country United States

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc22003748

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.

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$a Despite the development of novel targeted drugs, the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) still poses a substantial therapeutic challenge. DLBCL can be classified into at least 2 major subtypes (germinal center B cell [GCB]-like and activated B cell [ABC]-like DLBCL), each characterized by specific gene expression profiles and mutation patterns. Here we demonstrate a broad antitumor effect of dimethyl fumarate (DMF) on both DLBCL subtypes, which is mediated by the induction of ferroptosis, a form of cell death driven by the peroxidation of phospholipids. As a result of the high expression of arachidonate 5-lipoxygenase in concert with low glutathione and glutathione peroxidase 4 levels, DMF induces lipid peroxidation and thus ferroptosis, particularly in GCB DLBCL. In ABC DLBCL cells, which are addicted to NF-κB and STAT3 survival signaling, DMF treatment efficiently inhibits the activity of the IKK complex and Janus kinases. Interestingly, the BCL-2-specific BH3 mimetic ABT-199 and an inhibitor of ferroptosis suppressor protein 1 synergize with DMF in inducing cell death in DLBCL. Collectively, our findings identify the clinically approved drug DMF as a promising novel therapeutic option in the treatment of both GCB and ABC DLBCLs.
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$a dimethyl fumarát $x farmakologie $7 D000069462
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$a regulace genové exprese u nádorů $x účinky léků $7 D015972
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$a Xu, Wendan $u Department of Medicine A - Hematology, Oncology and Pneumology, University Hospital Münster, Muenster, Germany
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$a Bucher, Philip $u Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
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$a Grimm, Melanie $u Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
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$a Konantz, Martina $u Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland
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$a Horn, Heike $u Dr Margarete Fischer Bosch Institute of Clinical Pharmacology, University of Tübingen, Stuttgart, Germany $u Department of Clinical Pathology, Robert Bosch Krankenhaus, Stuttgart, Germany
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$a Zapukhlyak, Myroslav $u Department of Medicine A - Hematology, Oncology and Pneumology, University Hospital Münster, Muenster, Germany
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$a Berning, Philipp $u Department of Medicine A - Hematology, Oncology and Pneumology, University Hospital Münster, Muenster, Germany
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$a Brändle, Marc $u Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
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$a Jarboui, Mohamed-Ali $u Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
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$a Schönfeld, Caroline $u Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
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$a Boldt, Karsten $u Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
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$a Rosenwald, Andreas $u Institute of Pathology, Universität Würzburg-Comprehensive Cancer Center Mainfranken, Würzburg, Germany
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$a Ott, German $u Department of Clinical Pathology, Robert Bosch Krankenhaus, Stuttgart, Germany
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$a Grau, Michael $u Department of Medicine A - Hematology, Oncology and Pneumology, University Hospital Münster, Muenster, Germany
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$a Klener, Pavel $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic $u Hematology, First Department of Medicine, University General Hospital and First Faculty of Medicine, Charles University Prague, Prague, Czech Republic
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$a Vockova, Petra $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic $u Hematology, First Department of Medicine, University General Hospital and First Faculty of Medicine, Charles University Prague, Prague, Czech Republic
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$a Lengerke, Claudia $u Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland $u Internal Medicine II - Hematology, Oncology, Clinical Immunology and Rheumatology, Department for Internal Medicine, University Hospital Tübingen, Tübingen, Germany
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$a Lenz, Georg $u Department of Medicine A - Hematology, Oncology and Pneumology, University Hospital Münster, Muenster, Germany
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$a Schulze-Osthoff, Klaus $u Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany $u German Cancer Research Center, German Cancer Consortium, Heidelberg, Germany $u and Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany
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$a Hailfinger, Stephan $u Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany $u Department of Medicine A - Hematology, Oncology and Pneumology, University Hospital Münster, Muenster, Germany $u and Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany
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