The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; and.
Blood. 2013 Oct 10;122(15):2654-63. doi: 10.1182/blood-2013-02-484055. Epub 2013 Aug 27.
Deregulation of polycomb group complexes polycomb repressive complex 1 (PRC1) and 2 (PRC2) is associated with human cancers. Although inactivating mutations in PRC2-encoding genes EZH2, EED, and SUZ12 are present in T-cell acute lymphoblastic leukemia and in myeloid malignancies, gain-of-function mutations in EZH2 are frequently observed in B-cell lymphoma, implying disease-dependent effects of individual mutations. We show that, in contrast to PRC1, PRC2 is a tumor suppressor in Eµ-myc lymphomagenesis, because disease onset was accelerated by heterozygosity for Suz12 or by short hairpin RNA-mediated knockdown of Suz12 or Ezh2. Accelerated lymphomagenesis was associated with increased accumulation of B-lymphoid cells in the absence of effects on apoptosis or cell cycling. However, Suz12-deficient B-lymphoid progenitors exhibit enhanced serial clonogenicity. Thus, PRC2 normally restricts the self-renewal of B-lymphoid progenitors, the disruption of which contributes to lymphomagenesis. This finding provides new insight regarding the functional contribution of mutations in PRC2 in a range of leukemias.
多梳组复合物 polycomb repressive complex 1 (PRC1) 和 2 (PRC2) 的去调控与人类癌症有关。尽管 T 细胞急性淋巴细胞白血病和髓系恶性肿瘤中存在 PRC2 编码基因 EZH2、EED 和 SUZ12 的失活突变，但 EZH2 的功能获得性突变在 B 细胞淋巴瘤中经常观察到，这表明个体突变存在疾病依赖性效应。我们表明，与 PRC1 相反，PRC2 是 Eµ-myc 淋巴瘤发生中的肿瘤抑制因子，因为 Suz12 杂合性或 Suz12 或 Ezh2 的短发夹 RNA 介导的敲低会加速疾病的发生。加速的淋巴瘤发生与 B 淋巴细胞积累增加有关，而对细胞凋亡或细胞周期没有影响。然而，Suz12 缺陷的 B 淋巴细胞祖细胞表现出增强的连续克隆性。因此，PRC2 通常限制 B 淋巴细胞祖细胞的自我更新，其破坏有助于淋巴瘤的发生。这一发现为 PRC2 突变在一系列白血病中的功能贡献提供了新的见解。
