Journal Article

DKFZ-2023-01609

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png BRD4 inhibition sensitizes diffuse large B-cell lymphoma cells to ferroptosis

Schmitt, A. ; Grimm, M. ; Kreienkamp, N. ; Junge, H. ; Labisch, J. ; Schuhknecht, L. ; Schönfeld, C. ; Görsch, E. S. ; Tibello, A. ; Menck, K. ; Bleckmann, A. ; Lengerke, C. ; Rosenbauer, F. ; Grau, M. ; Zampieri, M. ; Schulze Osthoff, K.DKFZ* ; Klener, P. ; Dolnikova, A. ; Lenz, G. ; Hailfinger, S.

2023
American Society of Hematology Washington, DC

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Please use a persistent id in citations: doi:10.1182/blood.2022019274

Abstract: 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.

Note: 2023 Oct;12(10):e12363

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Tübingen (TU01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2023

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 20 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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