Diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma, is characterized by an aggressive clinical course. In approximately one-third of patients with DLBCL, first-line multiagent immunochemotherapy fails to produce a durable response. Molecular heterogeneity and apoptosis resistance pose major therapeutic challenges in DLBCL treatment. To circumvent apoptosis resistance, the induction of ferroptosis might represent a promising strategy for lymphoma therapy. In this study, a compound library, targeting epigenetic modulators, was screened to identify ferroptosis-sensitizing drugs. Strikingly, bromodomain and extra-terminal domain (BET) inhibitors sensitized cells of the germinal center B-cell-like (GCB) subtype of DLBCL to ferroptosis induction and the combination of BET inhibitors with ferroptosis inducers, such as dimethyl fumarate or RSL3, synergized in the killing of DLBCL cells in vitro and in vivo. On the molecular level, the BET protein BRD4 was found to be an essential regulator of ferroptosis suppressor protein 1 expression and thus to protect GCB-DLBCL cells from ferroptosis. Collectively, we identified and characterized BRD4 as an important player in ferroptosis suppression in GCB-DLBCL and provide a rationale for the combination of BET inhibitors with ferroptosis-inducing agents as a novel therapeutic approach for DLBCL treatment.

1st Department of Medicine Hematology University General Hospital and 1st Faculty of Medicine Charles University Prague Prague Czech Republic

Cluster of Excellence iFIT Image Guided and Functionally Instructed Tumor Therapies University of Tübingen Tübingen Germany

Department for Internal Medicine Internal Medicine 2 Hematology Oncology Clinical Immunology and Rheumatology University Hospital Tübingen Tübingen Germany

Department of Biomedicine University of Basel Basel Switzerland

Department of Medicine A Hematology Oncology and Pneumology University Hospital Münster Münster Germany

Department of Molecular Medicine Interfaculty Institute of Biochemistry University of Tübingen Tübingen Germany

German Cancer Consortium Heidelberg Germany

Institute of Molecular Tumor Biology Faculty of Medicine University of Münster Münster Germany

Institute of Pathological Physiology 1st Faculty of Medicine Charles University Prague Prague Czech Republic

Blood. 2023 Sep 28;142(13):1108-1109. doi: 10.1182/blood.2023021310. PubMed

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