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

Multi-agent chemotherapy still represents the first-line standard-of-care treatment for diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adults. However, the clinicopathological and molecular heterogeneity of DLBCLs poses a major challenge in their successful therapy. At least two major subtypes, i.e. germinal center B-cell-like (GCB) and the aggressive activated B-cell-like (ABC) DLBCL, which differ both in their gene expression profile and in their mutation patterns, have been identified. Here we demonstrate a broad inhibitory effect of dimethyl fumarate (DMF) on the outgrowth of both DLBCL subtypes, even though the molecular basis for its efficacy differs between GCB and ABC DLBCL. Due to high expression of arachidonate 5-lipoxygenase in concert with low glutathione and glutathione peroxidase 4 levels, DMF induced lipid peroxidation and thus ferroptotic cell death in GCB DLBCL. In contrast, in ABC DLBCL inhibition of NF-κB and STAT3 activity essentially contributed to DMF-dependent cytotoxicity. Interestingly, the BCL-2 specific BH3 mimetic ABT-199 or an inhibitor of the ferroptosis suppressor protein 1 synergized with DMF treatment in inducing cell death in DLBCL cell lines. Collectively, our findings identify the established and approved drug DMF as a promising novel therapeutic option in the treatment of both GCB and ABC DLBCL. Gene expression profiling was performed in HBL-1 cells after 6, 12, 24 and 48h of treatment with 20µM DMF, compared to control. Each time point was measured in triplicate, resulting in 24 samples in total.

多药联合化疗仍是成人最常见淋巴瘤类型——弥漫大B细胞淋巴瘤（diffuse large B-cell lymphoma, DLBCL）的一线标准治疗方案。然而，弥漫大B细胞淋巴瘤的临床病理与分子异质性，是其成功治疗面临的核心挑战。目前已鉴定出至少两种主要亚型，即生发中心B细胞样（germinal center B-cell-like, GCB）弥漫大B细胞淋巴瘤与侵袭性活化B细胞样（activated B-cell-like, ABC）弥漫大B细胞淋巴瘤，二者在基因表达谱与突变模式上均存在显著差异。本研究证实，富马酸二甲酯（dimethyl fumarate, DMF）对两种弥漫大B细胞淋巴瘤亚型的增殖均具有广泛抑制作用，尽管其发挥疗效的分子基础在GCB与ABC亚型中存在差异。在GCB亚型中，由于花生四烯酸5-脂氧合酶（arachidonate 5-lipoxygenase）高表达，同时谷胱甘肽与谷胱甘肽过氧化物酶4（glutathione peroxidase 4）水平较低，富马酸二甲酯可诱导脂质过氧化，进而引发铁死亡。与之相反，在ABC亚型中，核因子κB（NF-κB）与信号转导与转录激活因子3（STAT3）活性的抑制是富马酸二甲酯介导细胞毒性的核心贡献因素。值得注意的是，B细胞淋巴瘤因子2（B-cell lymphoma 2, BCL-2）特异性BH3模拟物ABT-199，或铁死亡抑制蛋白1（ferroptosis suppressor protein 1, FSP1）抑制剂，与富马酸二甲酯联合使用时，可协同诱导弥漫大B细胞淋巴瘤细胞系发生细胞死亡。综上，本研究证实，已获批上市的富马酸二甲酯可作为治疗GCB与ABC两种亚型弥漫大B细胞淋巴瘤的极具潜力的新型治疗选择。本研究对经20μM富马酸二甲酯处理6、12、24、48小时的HBL-1细胞进行了基因表达谱分析，并以未处理细胞作为对照。每个时间点均设置三次生物学重复，最终共计获得24份样本。