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

07:00 EST 3rd December 2019 | BioPortfolio

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

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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This article was published in the following journal.

Name: Blood
ISSN: 1528-0020
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Medical and Biotech [MESH] Definitions

A family of transcription factors characterized by the presence of highly conserved calcineurin- and DNA-binding domains. NFAT proteins are activated in the CYTOPLASM by the calcium-dependent phosphatase CALCINEURIN. They transduce calcium signals to the nucleus where they can interact with TRANSCRIPTION FACTOR AP-1 or NF-KAPPA B and initiate GENETIC TRANSCRIPTION of GENES involved in CELL DIFFERENTIATION and development. NFAT proteins stimulate T-CELL activation through the induction of IMMEDIATE-EARLY GENES such as INTERLEUKIN-2.

Compounds that inhibit or block the PHOSPHATASE activity of CALCINEURIN.

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