Targeting chronic NFAT activation with calcineurin inhibitors in diffuse large B-cell lymphoma

• Published in: Blood 2020-01, Vol.135 (2), p.121-132
• Main Authors: Bucher, Philip, Erdmann, Tabea, Grondona, Paula, Xu, Wendan, Schmitt, Anja, Schürch, Christoph, Zapukhlyak, Myroslav, Schönfeld, Caroline, Serfling, Edgar, Kramer, Daniela, Grau, Michael, Klener, Pavel, Lengerke, Claudia, Schulze-Osthoff, Klaus, Lenz, Georg, Hailfinger, Stephan
• Format: Article
• Language: English
• Subjects: Calcineurin - chemistry; Calcineurin Inhibitors - pharmacology; Calcium - metabolism; Cell Proliferation; Humans; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - metabolism; Lymphoma, Large B-Cell, Diffuse - pathology; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; NFATC Transcription Factors - antagonists & inhibitors; NFATC Transcription Factors - metabolism; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Tumor Cells, Cultured
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2019001866

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. •DLBCL cell lines exhibit chronic NFAT activation, which is independent of B-cell receptor-mediated signals.•Long-term treatment of ABC DLBCL with calcineurin inhibitors induces cytotoxicity and synergizes with BCL-2 and MCL-1 inhibition. [Display omitted]