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

Blood 2020 Jan 09

filter terms:

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. © 2020 by The American Society of Hematology.

Citation

Philip Bucher, Tabea Erdmann, Paula Grondona, Wendan Xu, Anja Schmitt, Christoph Schürch, Myroslav Zapukhlyak, Caroline Schönfeld, Edgar Serfling, Daniela Kramer, Michael Grau, Pavel Klener, Claudia Lengerke, Klaus Schulze-Osthoff, Georg Lenz, Stephan Hailfinger. Targeting chronic NFAT activation with calcineurin inhibitors in diffuse large B-cell lymphoma. Blood. 2020 Jan 09;135(2):121-132