TY  - JOUR
AU  - Schmitt, Anja
AU  - Grimm, Melanie
AU  - Kreienkamp, Nina
AU  - Junge, Hannah
AU  - Labisch, Jan
AU  - Schuhknecht, Laurentz
AU  - Schönfeld, Caroline
AU  - Görsch, Elsa Sophie
AU  - Tibello, Alessia
AU  - Menck, Kerstin
AU  - Bleckmann, Annalen
AU  - Lengerke, Claudia
AU  - Rosenbauer, Frank
AU  - Grau, Michael
AU  - Zampieri, Mattia
AU  - Schulze Osthoff, Klaus
AU  - Klener, Pavel
AU  - Dolnikova, Alexandra
AU  - Lenz, Georg
AU  - Hailfinger, Stephan
TI  - BRD4 inhibition sensitizes diffuse large B-cell lymphoma cells to ferroptosis
JO  - Blood
VL  - 12
IS  - 10
SN  - 0006-4971
CY  - Washington, DC
PB  - American Society of Hematology
M1  - DKFZ-2023-01609
SP  - e12363
PY  - 2023
N1  - 2023 Oct;12(10):e12363
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:37294920
DO  - DOI:10.1182/blood.2022019274
UR  - https://inrepo02.dkfz.de/record/278355
ER  -