弥漫性大B细胞淋巴瘤
生发中心
癌症研究
GPX4
细胞凋亡
淋巴瘤
化学
生物
富马酸二甲酯
程序性细胞死亡
谷胱甘肽
B细胞
谷胱甘肽过氧化物酶
免疫学
生物化学
抗体
酶
多发性硬化
作者
Anja Schmitt,Wendan Xu,Philip Bucher,Melanie Grimm,Martina Konantz,Heike Horn,Myroslav Zapukhlyak,Philipp Berning,Marc Brändle,Mohamed Ali Jarboui,Caroline Schönfeld,Karsten Boldt,Andreas Rosenwald,German Ott,Michael Grau,Pavel Klener,Petra Vočková,Claudia Lengerke,Georg Lenz,Klaus Schulze‐Osthoff,Stephan Hailfinger
出处
期刊:Blood
[American Society of Hematology]
日期:2021-04-19
卷期号:138 (10): 871-884
被引量:91
标识
DOI:10.1182/blood.2020009404
摘要
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.
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