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

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.

A New Ferroptosis-Related lncRNA Signature Predicts the Prognosis of Bladder Cancer Patients

“…Inhibition of NFS1 can induce ferroptosis and slow tumor growth in lung adenocarcinoma ( Alvarez et al, 2017 ). STAT3 is the target of ferroptosis in cancer cells, and impaired STAT3 signaling induces ferroptosis in diffuse large B-cell lymphoma cells ( Chen et al, 2021 ; Schmitt et al, 2021 ). Each patient’s risk score was calculated according to the formula.…”

Molecular Mechanisms of Ferroptosis and Its Roles in Hematologic Malignancies

“…DLBCL can be divided into two main subtypes of germinal center B cell-like (GCB) and aggressive activated B cell-like (ABC), both of which has their own specific gene expression profile and mutation pattern. Schmitt et al ( 129 ) investigated the antitumor mechanism of dimethyl fumarate (DMF) against DLBCL. Corresponding results revealed that DMF had a broad antitumor effect on both DLBCL subtypes, which is mediated by the induction of ferroptosis.…”

Construction and validation of a risk scoring model for diffuse large B-cell lymphoma based on ferroptosis-related genes and its association with immune infiltration

“…As an iron-catalyzed form of regulated necrosis, ferroptosis is involved in the silencing or downregulation of genes initiating or executing necroptosis in cancers [ 38 , 39 ]. DLBCL outcome is the result of interactions between the genetic abnormalities of ferroptosis-related factors and the clinical status of the patients [ 31 , 40 ]. Identification of clinical risk is helpful to better design the therapeutic intervention in different DLBCL patients [ 41 , 42 ].…”