Howard Hughes Medical Institute and Department of Pathology, New York University School of Medicine, New York, New York, USA.
Nat Med. 2012 Feb 6;18(2):298-301. doi: 10.1038/nm.2651.
T cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we report the presence of loss-of-function mutations and deletions of the EZH2 and SUZ12 genes, which encode crucial components of the Polycomb repressive complex 2 (PRC2), in 25% of T-ALLs. To further study the role of PRC2 in T-ALL, we used NOTCH1-dependent mouse models of the disease, as well as human T-ALL samples, and combined locus-specific and global analysis of NOTCH1-driven epigenetic changes. These studies demonstrated that activation of NOTCH1 specifically induces loss of the repressive mark Lys27 trimethylation of histone 3 (H3K27me3) by antagonizing the activity of PRC2. These studies suggest a tumor suppressor role for PRC2 in human leukemia and suggest a hitherto unrecognized dynamic interplay between oncogenic NOTCH1 and PRC2 function for the regulation of gene expression and cell transformation.
T 细胞急性淋巴细胞白血病（T-ALL）是一种不成熟的造血恶性肿瘤，主要由 NOTCH1 信号的致癌激活驱动。在这项研究中，我们报告了 25%的 T-ALL 中存在 EZH2 和 SUZ12 基因的功能丧失突变和缺失，这两种基因编码 Polycomb 抑制复合物 2（PRC2）的关键组成部分。为了进一步研究 PRC2 在 T-ALL 中的作用，我们使用了依赖 NOTCH1 的疾病小鼠模型以及人类 T-ALL 样本，并对 NOTCH1 驱动的表观遗传变化进行了局部和全局分析。这些研究表明，NOTCH1 的激活通过拮抗 PRC2 的活性，特异性地诱导组蛋白 H3K27me3 的抑制标记赖氨酸 27 三甲基化（H3K27me3）的丢失。这些研究提示 PRC2 在人类白血病中发挥肿瘤抑制作用，并提示致癌 NOTCH1 和 PRC2 功能之间存在一种迄今为止尚未被认识的动态相互作用，用于调节基因表达和细胞转化。
