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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Abstract
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) |
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UniBasel Contributors: | Konantz, Martina |
Item Type: | Article, refereed |
Article Subtype: | Research Article |
Publisher: | American Society of Hematology |
ISSN: | 0006-4971 |
Note: | Publication type according to Uni Basel Research Database: Journal article |
Identification Number: |
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Last Modified: | 27 Jan 2022 15:39 |
Deposited On: | 27 Jan 2022 15:39 |
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