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

Schmitt, Anja and Xu, Wendan and Bucher, Philip and Grimm, Melanie and Konantz, Martina and Horn, Heike and Zapukhlyak, Myroslav and Berning, Philipp and Brändle, Marc and Jarboui, Mohamed-Ali and Schönfeld, Caroline and Boldt, Karsten and Rosenwald, Andreas and Ott, German and Grau, Michael and Klener, Pavel and Vockova, Petra and Lengerke, Claudia and Lenz, Georg and Schulze-Osthoff, Klaus and Hailfinger, Stephan. (2021) Dimethyl fumarate induces ferroptosis and impairs NF-κB/STAT3 signaling in DLBCL. Blood, 138 (10). pp. 871-884.

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Official URL: https://edoc.unibas.ch/83867/

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Despite the development of novel targeted drugs, the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) still poses a major therapeutic challenge. DLBCL can be classified into at least two major subtypes, i.e. germinal center B-cell-like (GCB) and the aggressive activated B-cell-like (ABC) DLBCL, each characterized by specific gene expression profiles and mutation patterns. Here we demonstrate a broad anti-tumor 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. Due to 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 JAK 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 DLBCL.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Stem Cells and Hematopoiesis (Lengerke)
UniBasel Contributors:Konantz, Martina
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society of Hematology
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:27 Jan 2022 15:39
Deposited On:27 Jan 2022 15:39

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