Calcineurin-independent NFATc1 signaling is essential for survival of Burkitt lymphoma cells

Krisna Murti; Hendrik Fender; Carolin Glatzle; Rhoda Wismer; Salvador Sampere-Birlanga; Vanessa Wild; Khalid Muhammad; Andreas Rosenwald; Edgar Serfling; Andris Avots

doi:10.3389/fonc.2023.1205788

Calcineurin-independent NFATc1 signaling is essential for survival of Burkitt lymphoma cells

Front Oncol. 2023 Jul 21:13:1205788. doi: 10.3389/fonc.2023.1205788. eCollection 2023.

Affiliation

¹ Department of Molecular Pathology, Institute of Pathology, and Comprehensive Cancer Center Mainfranken, Julius-Maximilians University of Wuerzburg, Wuerzburg, Germany.

Abstract

In Burkitt lymphoma (BL), a tumor of germinal center B cells, the pro-apoptotic properties of MYC are controlled by tonic B cell receptor (BCR) signals. Since BL cells do not exhibit constitutive NF-κB activity, we hypothesized that anti-apoptotic NFATc1 proteins provide a major transcriptional survival signal in BL. Here we show that post-transcriptional mechanisms are responsible for the calcineurin (CN) independent constitutive nuclear over-expression of NFATc1 in BL and Eµ-MYC - induced B cell lymphomas (BCL). Conditional inactivation of the Nfatc1 gene in B cells of Eµ-MYC mice leads to apoptosis of BCL cells in vivo and ex vivo. Inhibition of BCR/SYK/BTK/PI3K signals in BL cells results in cytosolic re-location of NFATc1 and apoptosis. Therefore, NFATc1 activity is an integrated part of tonic BCR signaling and an alternative target for therapeutic intervention in BL.

Keywords: B cell receptor (BCR); Burkitt lymphoma; Burkitt lymphoma (BL); NFATc1; activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL); apoptosis; cyclosporin A; nuclear localization.