Diffuse large B-cell lymphoma (DLBCL) represents the most common adult lymphoma and can be divided into 2 major molecular subtypes: the germinal center B-cell-like and the aggressive activated B-cell-like (ABC) DLBCL. Previous studies suggested that chronic B-cell receptor signaling and increased NF-κB activation contribute to ABC DLBCL survival. Here we show that the activity of the transcription factor NFAT is chronically elevated in both DLBCL subtypes. Surprisingly, NFAT activation is independent of B-cell receptor signaling, but mediated by an increased calcium flux and calcineurin-mediated dephosphorylation of NFAT. Intriguingly, although NFAT is activated in both DLBCL subtypes, long-term calcineurin inhibition with cyclosporin A or FK506, both clinically approved drugs, triggers potent cytotoxicity specifically in ABC DLBCL cells. The antitumor effects of calcineurin inhibitors are associated with the reduced expression of c-Jun, interleukin-6, and interleukin-10, which were identified as NFAT target genes that are particularly important for the survival of ABC DLBCL. Furthermore, calcineurin blockade synergized with BCL-2 and MCL-1 inhibitors in killing ABC DLBCL cells. Collectively, these findings identify constitutive NFAT signaling as a crucial functional driver of ABC DLBCL and highlight calcineurin inhibition as a novel strategy for the treatment of this aggressive lymphoma subtype.

Cluster of Excellence iFIT Image Guided and Functionally Instructed Tumor Therapies University of Tübingen Tübingen Germany

Department of Biomedicine University Hospital and University of Basel Basel Switzerland

Department of Hematology Charles University General Hospital Prague Prague Czech Republic

Department of Medicine A Hematology Oncology and Pneumology University Hospital Münster Münster Germany

Department of Molecular Pathology University of Würzburg Würzburg Germany

Division of Hematology University Hospital Basel Basel Switzerland

German Cancer Consortium Heidelberg Germany

German Cancer Research Center Heidelberg Germany; and

Institute of Pathological Physiology 1st Faculty of Medicine and

Interfaculty Institute for Biochemistry Eberhard Karls University Tübingen Germany

Blood. 2020 Jan 9;135(2):81. doi: 10.1182/blood.2019004199. PubMed

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