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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

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

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  • Media type: E-Article
  • Title: Targeting chronic NFAT activation with calcineurin inhibitors in diffuse large B-cell lymphoma
  • Contributor: 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
  • imprint: American Society of Hematology, 2020
  • Published in: Blood
  • Language: English
  • DOI: 10.1182/blood.2019001866
  • ISSN: 0006-4971; 1528-0020
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>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.</jats:p>
  • Access State: Open Access