突变 EZH2 通过重塑免疫反应诱导恶性前淋巴瘤生态位。
Mutant EZH2 Induces a Pre-malignant Lymphoma Niche by Reprogramming the Immune Response.
机构信息
Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA.
Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Institute for Computational Biomedicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA.
出版信息
Cancer Cell. 2020 May 11;37(5):655-673.e11. doi: 10.1016/j.ccell.2020.04.004.
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.
滤泡性淋巴瘤（FL）是一种生长缓慢、惰性的肿瘤，含有广泛的滤泡树突状细胞（FDC）网络和反复出现的 EZH2 功能获得性突变。矛盾的是，FL 起源于高度增殖的生发中心（GC）B 细胞，其增殖严格依赖于与 T 滤泡辅助细胞的相互作用。在此，我们表明 EZH2 突变通过削弱 GC B 细胞对 T 细胞辅助的需求并驱动 GC 中心母细胞的缓慢扩增来启动 FL，这些细胞与 FDC 纠缠并依赖于 FDC。通过损害 T 细胞辅助，突变型 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 细胞形成异常的免疫微环境来促进恶性转化，这种免疫微环境反映了人类 FL 的特征，解释了惰性肿瘤如何从 GC B 细胞中产生。
Zotero 插件