Murti Krisna, Fender Hendrik, Glatzle Carolin, Wismer Rhoda, Sampere-Birlanga Salvador, Wild Vanessa, Muhammad Khalid, Rosenwald Andreas, Serfling Edgar, Avots Andris
Department of Molecular Pathology, Institute of Pathology, and Comprehensive Cancer Center Mainfranken, Julius-Maximilians University of Wuerzburg, Wuerzburg, Germany.
Front Oncol. 2023 Jul 21;13:1205788. doi: 10.3389/fonc.2023.1205788. eCollection 2023.
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-B 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 - induced B cell lymphomas (BCL). Conditional inactivation of the gene in B cells of mice leads to apoptosis of BCL cells and . 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.
在生发中心B细胞肿瘤——伯基特淋巴瘤（BL）中，MYC的促凋亡特性受持续性B细胞受体（BCR）信号控制。由于BL细胞不表现出组成型核因子-κB（NF-κB）活性，我们推测抗凋亡的活化T细胞核因子c1（NFATc1）蛋白在BL中提供了主要的转录生存信号。在此我们表明，转录后机制导致了NFATc1在BL和EB病毒诱导的B细胞淋巴瘤（BCL）中不依赖钙调神经磷酸酶（CN）的组成型核内过表达。在Eμ-Myc小鼠的B细胞中条件性失活该基因会导致BCL细胞凋亡。抑制BL细胞中的BCR/脾酪氨酸激酶（SYK）/布鲁顿酪氨酸激酶（BTK）/磷脂酰肌醇-3-激酶（PI3K）信号会导致NFATc1的胞质重新定位和细胞凋亡。因此，NFATc1活性是持续性BCR信号的一个组成部分，也是BL治疗干预的一个替代靶点。
