Immunoglobulin class-switching from IgM to IgG enhances B cell receptor (BCR) signalling and promotes germinal centre (GC) B cell responses to antigens. In contrast, non-Hodgkin lymphomas derived from GC B cells typically avoid IgG BCR expression and retain the unswitched IgM BCR, suggesting that IgG BCR may protect B cells from malignant transformation. However, the mechanism of this phenomenon and its significance for the pathogenicity of IgG-expressing lymphomas remains unclear. Here, we report that IgG-positive follicular lymphoma (FL) and the related EZB subset of diffuse large B cell lymphoma (DLBCL) acquire mutations in the IgG heavy chain, disrupting its unique intracellular tail. Enforced class switching of IgM-expressing EZB DLBCL cell lines to IgG reduces BCR surface levels, signalling via phosphoinositide-3 kinase (PI3K), levels of MYC, cell proliferation and in vivo growth. Inhibiting GSK3, a target of BCR-PI3K signalling, or stimulating the BCR rescues IgG+ cell proliferation. In contrast, IgG tail-truncating mutations enhance BCR surface expression, intracellular signalling and competitive growth. These findings suggest that the expansion of IgG-switched GC-like B lymphoma cells is limited by low tonic PI3K activity of the wild-type IgG BCR, but a subset of these cancers acquires mutations of the IgG intracellular tail that reverse this effect, promoting the oncogenicity of their BCRs. The presence of IgG tail mutations underscores the importance of isotype-specific BCR signalling in the pathogenesis of FL and EZB DLBCL and can potentially inform therapeutic targeting with BCR signalling inhibitors or antibody-drug conjugates.

中文翻译：

---

与类别转换 B 细胞淋巴瘤相关的 IgG B 细胞受体突变

免疫球蛋白类别从 IgM 转换为 IgG 可增强 B 细胞受体 (BCR) 信号传导并促进生发中心 (GC) B 细胞对抗原的反应。相比之下，源自GC B细胞的非霍奇金淋巴瘤通常避免IgG BCR表达并保留未转换的IgM BCR，这表明IgG BCR可以保护B细胞免于恶性转化。然而，这种现象的机制及其对表达 IgG 的淋巴瘤致病性的意义仍不清楚。在此，我们报告 IgG 阳性滤泡性淋巴瘤 (FL) 和相关的弥漫性大 B 细胞淋巴瘤 (DLBCL) EZB 亚型在 IgG 重链中发生突变，破坏其独特的细胞内尾部。将表达 IgM 的 EZB DLBCL 细胞系强制转换为 IgG，可降低 BCR 表面水平、通过磷酸肌醇 3 激酶 (PI3K) 发出的信号、MYC 水平、细胞增殖和体内生长。抑制 BCR-PI3K 信号传导靶点 GSK3 或刺激 BCR 可挽救 IgG+ 细胞增殖。相反，IgG 尾部截短突变增强了 BCR 表面表达、细胞内信号传导和竞争性生长。这些发现表明，IgG 转换的 GC 样 B 淋巴瘤细胞的扩增受到野生型 IgG BCR 的低强 PI3K 活性的限制，但这些癌症的一部分获得了 IgG 细胞内尾部的突变，从而逆转了这种效应，促进了其 BCR 的致癌性。 IgG 尾部突变的存在强调了同种型特异性 BCR 信号在 FL 和 EZB DLBCL 发病机制中的重要性，并可能为 BCR 信号抑制剂或抗体药物偶联物的治疗靶向提供信息。