Clinic of Haematology and Medical Oncology, University Medical Centre Göttingen, Lower Saxony, 37075, Göttingen, Germany.
Network BMBF eBio MMML MYC-SYS, 37099 Göttingen / 93053 Regensburg, Germany.
Nat Commun. 2018 Apr 17;9(1):1514. doi: 10.1038/s41467-018-03803-x.
Knowledge of stromal factors that have a role in the transcriptional regulation of metabolic pathways aside from c-Myc is fundamental to improvements in lymphoma therapy. Using a MYC-inducible human B-cell line, we observed the cooperative activation of STAT3 and NF-κB by IL10 and CpG stimulation. We show that IL10 + CpG-mediated cell proliferation of MYC cells depends on glutaminolysis. By C- and N-tracing of glutamine metabolism and metabolite rescue experiments, we demonstrate that GOT2 provides aspartate and nucleotides to cells with activated or aberrant Jak/STAT and NF-κB signaling. A model of GOT2 transcriptional regulation is proposed, in which the cooperative phosphorylation of STAT3 and direct joint binding of STAT3 and p65/NF-κB to the proximal GOT2 promoter are important. Furthermore, high aberrant GOT2 expression is prognostic in diffuse large B-cell lymphoma underscoring the current findings and importance of stromal factors in lymphoma biology.
除了 c-Myc 之外，了解在转录调控代谢途径中起作用的基质因子对于改善淋巴瘤治疗至关重要。我们使用一种 MYC 诱导的人 B 细胞系，观察到 IL10 和 CpG 刺激协同激活 STAT3 和 NF-κB。我们表明，IL10+C pG 介导的 MYC 细胞增殖依赖于谷氨酰胺分解代谢。通过谷氨酰胺代谢的 C 和 N 追踪以及代谢物挽救实验，我们证明 GOT2 为激活或异常 Jak/STAT 和 NF-κB 信号转导的细胞提供天冬氨酸和核苷酸。提出了 GOT2 转录调控的模型，其中 STAT3 的协同磷酸化以及 STAT3 和 p65/NF-κB 的直接联合结合到 GOT2 启动子的近端对于该模型很重要。此外，弥漫性大 B 细胞淋巴瘤中异常高的 GOT2 表达具有预后意义，突出了当前发现以及基质因子在淋巴瘤生物学中的重要性。
