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

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

  • Bucher P Interfaculty Institute for Biochemistry, Eberhard Karls University, Tübingen, Germany.
  • Erdmann T Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany.
  • Grondona P Interfaculty Institute for Biochemistry, Eberhard Karls University, Tübingen, Germany.
  • Xu W Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany.
  • Schmitt A Interfaculty Institute for Biochemistry, Eberhard Karls University, Tübingen, Germany.
  • Schürch C Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland.
  • Zapukhlyak M Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany.
  • Schönfeld C Interfaculty Institute for Biochemistry, Eberhard Karls University, Tübingen, Germany.
  • Serfling E Department of Molecular Pathology, University of Würzburg, Würzburg, Germany.
  • Kramer D Interfaculty Institute for Biochemistry, Eberhard Karls University, Tübingen, Germany.
  • Grau M Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany.
  • Klener P Institute of Pathological Physiology, First Faculty of Medicine, and.
  • Lengerke C Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland.
  • Schulze-Osthoff K Interfaculty Institute for Biochemistry, Eberhard Karls University, Tübingen, Germany.
  • Lenz G Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany.
  • Hailfinger S Interfaculty Institute for Biochemistry, Eberhard Karls University, Tübingen, Germany.
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  • 2019-12-04
Published in:
  • Blood. - 2020
Calcineurin
Calcineurin Inhibitors
Calcium
Cell Proliferation
Humans
Lymphoma, Large B-Cell, Diffuse
Myeloid Cell Leukemia Sequence 1 Protein
NFATC Transcription Factors
Proto-Oncogene Proteins c-bcl-2
Tumor Cells, Cultured
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/231741
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