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

ABSTRACT: Metabolomic analysis of BET inhibitor treated DLBCL cells: DOHH2 and WSU-DLCL-2 cells were treated with JQ1, I-BET151 or I-BET762 for 24 h. The cellular concentrations of the indicated metabolites were quantified by mass spectrometry and normalized to the solvent control.

ORGANISM(S): Homo sapiens (human)

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PROVIDER: S-BSST1072 | biostudies-other |

REPOSITORIES: biostudies-other

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

Project description: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 DLBCL patients, first-line multi-agent 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. Here, 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 (DMF) 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 (FSP1) expression and to thus 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.

2023-08-01 | GSE231871 | GEO

Inhibition of demethylase KDM6B sensitizes diffuse large B-cell lymphoma to chemotherapeutic drugs.