The transcription factor forkhead box O1 (FOXO1), which instructs the dark zone program to direct germinal center (GC) polarity, is typically inactivated by phosphatidylinositol 3-kinase (PI3K) signals. Here, we investigated how FOXO1 mutations targeting this regulatory axis in GC-derived B cell non-Hodgkin lymphomas (B-NHLs) contribute to lymphomagenesis. Examination of primary B-NHL tissues revealed that FOXO1 mutations and PI3K pathway activity were not directly correlated. Human B cell lines bearing FOXO1 mutations exhibited hyperactivation of PI3K and Stress-activated protein kinase (SAPK)/Jun amino-terminal kinase (JNK) signaling, and increased cell survival under stress conditions as a result of alterations in FOXO1 transcriptional affinities and activation of transcriptional programs characteristic of GC-positive selection. When modeled in mice, FOXO1 mutations conferred competitive advantage to B cells in response to key T-dependent immune signals, disrupting GC homeostasis. FOXO1 mutant transcriptional signatures were prevalent in human B-NHL and predicted poor clinical outcomes. Thus, rather than enforcing FOXO1 constitutive activity, FOXO1 mutations enable co-option of GC-positive selection programs during the pathogenesis of GC-derived lymphomas.

指示暗区程序引导生发中心 (GC) 极性的转录因子叉头盒 O1 (FOXO1) 通常被磷脂酰肌醇 3-激酶 (PI3K) 信号灭活。在这里，我们研究了在 GC 衍生的 B 细胞非霍奇金淋巴瘤 (B-NHLs) 中针对该调节轴的FOXO1突变如何导致淋巴瘤发生。对原发性 B-NHL 组织的检查显示FOXO1突变和 PI3K 通路活性不直接相关。携带FOXO1的人类 B 细胞系突变表现出 PI3K 和应激激活蛋白激酶 (SAPK)/Jun 氨基末端激酶 (JNK) 信号传导的过度激活，并且由于 FOXO1 转录亲和力的改变和 GC- 特征的转录程序的激活而增加了应激条件下的细胞存活率积极的选择。在小鼠中建模时，FOXO1突变赋予 B 细胞竞争优势，以响应关键的 T 依赖性免疫信号，破坏 GC 稳态。FOXO1 突变转录特征在人类 B-NHL 中普遍存在，并且预测临床结果不佳。因此，FOXO1 突变不是强制 FOXO1 组成活性，而是在 GC 衍生淋巴瘤的发病过程中启用 GC 阳性选择程序的共同选择。