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

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

. 2023 ; 142 (13) : 1143-1155. [pub] 2023Sep28

Language English Country United States

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc23016181

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.

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$a Diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma, is characterized by an aggressive clinical course. In approximately one-third of patients with DLBCL, first-line multiagent immunochemotherapy fails to produce a durable response. Molecular heterogeneity and apoptosis resistance pose major therapeutic challenges in DLBCL treatment. To circumvent apoptosis resistance, the induction of ferroptosis might represent a promising strategy for lymphoma therapy. In this study, a compound library, targeting epigenetic modulators, was screened to identify ferroptosis-sensitizing drugs. Strikingly, bromodomain and extra-terminal domain (BET) inhibitors sensitized cells of the germinal center B-cell-like (GCB) subtype of DLBCL to ferroptosis induction and the combination of BET inhibitors with ferroptosis inducers, such as dimethyl fumarate or RSL3, synergized in the killing of DLBCL cells in vitro and in vivo. On the molecular level, the BET protein BRD4 was found to be an essential regulator of ferroptosis suppressor protein 1 expression and thus to protect GCB-DLBCL cells from ferroptosis. Collectively, we identified and characterized BRD4 as an important player in ferroptosis suppression in GCB-DLBCL and provide a rationale for the combination of BET inhibitors with ferroptosis-inducing agents as a novel therapeutic approach for DLBCL treatment.
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$a Grimm, Melanie $u Department of Molecular Medicine, Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
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$a Kreienkamp, Nina $u Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany
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$a Schuhknecht, Laurentz $u Department of Biomedicine, University of Basel, Basel, Switzerland
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$a Schönfeld, Caroline $u Department of Molecular Medicine, Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
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$a Görsch, Elsa $u Department for Internal Medicine, Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
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$a Tibello, Alessia $u Institute of Molecular Tumor Biology, Faculty of Medicine, University of Münster, Münster, Germany
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$a Menck, Kerstin $u Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany $1 https://orcid.org/0000000281880163
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$a Bleckmann, Annalen $u Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany
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$a Lengerke, Claudia $u Department for Internal Medicine, Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany $1 https://orcid.org/0000000154422805
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$a Rosenbauer, Frank $u Institute of Molecular Tumor Biology, Faculty of Medicine, University of Münster, Münster, Germany
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$a Grau, Michael $u Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany
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$a Zampieri, Mattia $u Department of Biomedicine, University of Basel, Basel, Switzerland $1 https://orcid.org/000000029339068X
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$a Schulze-Osthoff, Klaus $u Department of Molecular Medicine, Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany $u German Cancer Consortium (Deutsches Konsortium für Translationale Krebsforschung) and German Cancer Research Center (Deutsches Krebsforschungszentrum), Heidelberg, Germany $u Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany
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$a Dolnikova, Alexandra $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic $1 https://orcid.org/0000000259826523
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$a Lenz, Georg $u Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany
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$a Hailfinger, Stephan $u Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany
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