Due to low glutathione and GPX4 levels in concert with high 5-LOX expression, DMF potently induces ferroptosis in GCB DLBCL.
In ABC DLBCL, DMF induces succination of the kinases IKK2 and JAK1, thus inhibiting NF-κB and JAK/STAT survival signaling.
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.