Follicular lymphomas (FLs) are slow-growing, indolent tumors containing extensive follicular dendritic cell (FDC) networks and recurrent EZH2 gain-of-function mutations. Paradoxically, FLs originate from highly proliferative germinal center (GC) B cells with proliferation strictly dependent on interactions with T follicular helper cells. Herein, we show that EZH2 mutations initiate FL by attenuating GC B cell requirement for T cell help and driving slow expansion of GC centrocytes that become enmeshed with and dependent on FDCs. By impairing T cell help, mutant EZH2 prevents induction of proliferative MYC programs. Thus, EZH2 mutation fosters malignant transformation by epigenetically reprograming B cells to form an aberrant immunological niche that reflects characteristic features of human FLs, explaining how indolent tumors arise from GC B cells.

中文翻译：

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突变的EZH2通过重新编程免疫应答诱导恶性前淋巴瘤的生态位。

滤泡性淋巴瘤（FLs）是生长缓慢的惰性肿瘤，包含广泛的滤泡性树突状细胞（FDC）网络和复发性EZH2功能获得性突变。矛盾的是，FLs起源于高度增殖的生发中心（GC）B细胞，其增殖严格取决于与T滤泡辅助细胞的相互作用。在本文中，我们显示EZH2突变通过减弱T细胞帮助的GC B细胞需求并驱动缓慢陷入与FDC依赖的GC中心细胞的扩张来启动FL。通过削弱T细胞的帮助，突变体EZH2阻止了增殖性MYC程序的诱导。因此，EZH2突变通过表观遗传重编程B细胞以形成反映人FLs特征的异常免疫位，从而促进恶性转化，从而解释了GC B细胞是如何产生惰性肿瘤的。