Key Points

  • DLBCL cell lines exhibit chronic NFAT activation, which is independent of BCR-mediated signals.

  • Long-term treatment of ABC DLBCL with calcineurin inhibitors induces cytotoxicity and synergizes with BCL-2 and MCL-1 inhibitors.

Diffuse large B-cell lymphoma (DLBCL) represents the most common adult lymphoma that is divided into two major molecular subtypes, the germinal center B-cell-like (GCB) and the aggressive activated B-cell-like (ABC) DLBCL. Previous studies suggested that chronic BCR signaling and increased NF-κB activation contribute to ABC DLBCL. Here we show that the activity of the transcription factor NFAT is chronically elevated in both DLBCL subtypes. Surprisingly, NFAT activation was independent of BCR signaling, but mediated by an increased calcium flux and calcineurin-mediated dephosphorylation of NFAT. Intriguingly, although NFAT was activated in both DLBCL subtypes, long-term calcineurin inhibition by cyclosporin A or FK506, both clinically approved drugs, triggered potent cytotoxicity specifically in ABC DLBCL cells. The antitumor effects of calcineurin inhibitors were associated with the downregulation of c-Jun, IL-6 and IL-10, which were identified as NFAT target genes particularly important for 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 ABC DLBCL.

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