PUBLICATION
Dimethyl fumarate induces ferroptosis and impairs NF-κB/STAT3 signaling in DLBCL
- Authors
- Schmitt, A., Xu, W., Bucher, P., Grimm, M., Konantz, M., Horn, H., Zapukhlyak, M., Berning, P., Brändle, M., Jarboui, M.A., Schönfeld, C., Boldt, K., Rosenwald, A., Ott, G., Grau, M., Klener, P., Vockova, P., Lengerke, C., Lenz, G., Schulze-Osthoff, K., Hailfinger, S.
- ID
- ZDB-PUB-211216-20
- Date
- 2021
- Source
- Blood 138: 871-884 (Journal)
- Registered Authors
- Konantz, Martina, Lengerke, Claudia
- Keywords
- none
- MeSH Terms
-
- Animals
- Dimethyl Fumarate/pharmacology*
- Ferroptosis/drug effects*
- Gene Expression Regulation, Neoplastic/drug effects
- Humans
- Lipid Peroxidation/drug effects
- Lipid Peroxidation/genetics
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Lymphoma, Large B-Cell, Diffuse/genetics
- Lymphoma, Large B-Cell, Diffuse/metabolism*
- Lymphoma, Large B-Cell, Diffuse/pathology
- Mice
- NF-kappa B/genetics
- NF-kappa B/metabolism*
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism*
- STAT3 Transcription Factor/genetics
- STAT3 Transcription Factor/metabolism*
- Signal Transduction/drug effects*
- Signal Transduction/genetics
- Xenograft Model Antitumor Assays
- Zebrafish
- PubMed
- 33876201 Full text @ Blood
Citation
Schmitt, A., Xu, W., Bucher, P., Grimm, M., Konantz, M., Horn, H., Zapukhlyak, M., Berning, P., Brändle, M., Jarboui, M.A., Schönfeld, C., Boldt, K., Rosenwald, A., Ott, G., Grau, M., Klener, P., Vockova, P., Lengerke, C., Lenz, G., Schulze-Osthoff, K., Hailfinger, S. (2021) Dimethyl fumarate induces ferroptosis and impairs NF-κB/STAT3 signaling in DLBCL. Blood. 138:871-884.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping