Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA.
Cancer Cell. 2013 May 13;23(5):677-92. doi: 10.1016/j.ccr.2013.04.011.
The EZH2 histone methyltransferase is highly expressed in germinal center (GC) B cells and targeted by somatic mutations in B cell lymphomas. Here, we find that EZH2 deletion or pharmacologic inhibition suppresses GC formation and functions. EZH2 represses proliferation checkpoint genes and helps establish bivalent chromatin domains at key regulatory loci to transiently suppress GC B cell differentiation. Somatic mutations reinforce these physiological effects through enhanced silencing of EZH2 targets. Conditional expression of mutant EZH2 in mice induces GC hyperplasia and accelerated lymphomagenesis in cooperation with BCL2. GC B cell (GCB)-type diffuse large B cell lymphomas (DLBCLs) are mostly addicted to EZH2 but not the more differentiated activated B cell (ABC)-type DLBCLs, thus clarifying the therapeutic scope of EZH2 targeting.
EZH2 组蛋白甲基转移酶在生发中心 (GC) B 细胞中高度表达，并受到 B 细胞淋巴瘤体细胞突变的靶向作用。在这里，我们发现 EZH2 的缺失或药物抑制可抑制 GC 的形成和功能。EZH2 抑制增殖检查点基因，并有助于在关键调控基因座建立双价染色质结构域，以暂时抑制 GC B 细胞分化。体细胞突变通过增强 EZH2 靶基因的沉默来强化这些生理效应。在小鼠中条件性表达突变型 EZH2 可与 BCL2 共同诱导 GC 增生和加速淋巴瘤发生。GC B 细胞（GCB）型弥漫性大 B 细胞淋巴瘤（DLBCL）大多依赖于 EZH2，但不依赖于分化程度更高的激活 B 细胞（ABC）型 DLBCL，从而明确了 EZH2 靶向治疗的范围。
