Details

Autor(en) / Beteiligte

• Schmitt, Anja
• Grimm, Melanie
• Kreienkamp, Nina
• Junge, Hannah
• Labisch, Jan
• Schuhknecht, Laurentz
• Schönfeld, Caroline
• Görsch, Elsa
• Tibello, Alessia
• Menck, Kerstin
• Bleckmann, Annalen
• Lengerke, Claudia
• Rosenbauer, Frank
• Grau, Michael
• Zampieri, Mattia
• Schulze-Osthoff, Klaus
• Klener, Pavel
• Dolnikova, Alexandra
• Lenz, Georg
• Hailfinger, Stephan

Titel

BRD4 inhibition sensitizes diffuse large B-cell lymphoma cells to ferroptosis

Ist Teil von

• Blood, 2023-09, Vol.142 (13), p.1143-1155

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• •BRD4 protects DLBCL cells from ferroptosis by positively regulating the expression of FSP1.•BET inhibitors increase the susceptibility of GCB-DLBCL cells to ferroptosis and thus promote the toxicity of DMF both in vitro and in vivo. [Display omitted] 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. First-line immunochemotherapy for diffuse large B-cell lymphoma (DLBCL) fails to produce a durable remission in about one-third of patients. Previous studies have suggested that the germinal center B-cell-like subset of DLBCL is sensitive to triggering of ferroptosis (iron-mediated cell death). Schmitt and colleagues screened a library of epigenetic modulators and demonstrate that bromodomain and extraterminal domain (BET) inhibitors enhance ferroptosis, suggesting the combination of BET inhibitors and ferroptosis-inducing agents as a novel therapy for DLBCL.