在滤泡性淋巴瘤（FL）起源的早期事件中，由于基因重排和/或体细胞高度变异，B细胞受体（BCR）中的糖基化模式发生变化是其发生的一个重要因素。这些N-连接糖基化模式（N-模式）包含甘露糖末端糖基，可以与肿瘤微环境中的凝留素发生相互作用，从而激活肿瘤BCR通路。N-模式在FL进化过程中是稳定的，表明FL肿瘤细胞对它们的生存起到了依赖作用。本研究在17例患者的不同肿瘤部位和时间点上，以单细胞水平调查了N-模式在FL中的动态和潜在影响。虽然大多数患者在早期事件中至少获得了一种N-模式，但我们还发现（i）在任何肿瘤部位或时间点上都没有重链或轻链中的N-模式的病例，以及（ii）在不同肿瘤部位表现出不一致的N-模式的情况。通过对具有不一致模式的患者进行系统发育树推断，我们观察到在肿瘤进化过程中，无论是N-模式阳性还是阴性的肿瘤亚克隆都可能被选择和扩展。在同一患者内，将N-模式阳性和阴性的肿瘤细胞进行比较，发现与N-模式无关的肿瘤细胞表达了与BCR通路和炎症反应有关的基因更高，而没有N-模式的肿瘤细胞则在能量代谢相关途径上的活性更高。总之，虽然在大多数FL患者中，获得的N-模式可能通过抗原无关的BCR信号传导来支持FL的发病机制，但无N-模式的肿瘤细胞也可以被选择和扩展，并且可能更依赖于代谢改变来竞争性生存。版权所有©2023年美国血液学会。

An early event in the genesis of follicular lymphoma (FL) is the acquisition of new glycosylation motifs in the B cell receptor (BCR) due to gene rearrangement and/or somatic hypermutation. These N-linked glycosylation motifs (N-motifs) contain mannose-terminated glycans and can interact with lectins in the tumor microenvironment, activating the tumor BCR pathway. N-motifs are stable during FL evolution suggesting that FL tumor cells are dependent on them for their survival. Here, we investigated the dynamics and potential impact of N-motif prevalence in FL at the single cell level across distinct tumor sites and over time in 17 patients. While most patients had acquired at least one N-motif as an early event, we also found (i) cases without N-motifs in the heavy or light chains at any tumor site or timepoint and (ii) cases with discordant N-motif patterns across different tumor sites. Inferring phylogenetic trees for the patients with discordant patterns, we observed that both N-motif-positive and N-motif-negative tumor subclones could be selected and expanded during tumor evolution. Comparing N-motif-positive to N-motif-negative tumor cells within a patient revealed higher expression of genes involved in the BCR pathway and inflammatory response, while tumor cells without N-motifs had higher activity of pathways involved in energy metabolism. In conclusion, while acquired N-motifs likely support FL pathogenesis through antigen-independent BCR signaling in most FL patients, N-motif-negative tumor cells can also be selected and expanded and may depend more heavily on altered metabolism for competitive survival.Copyright © 2023 American Society of Hematology.