Oncogene addiction of ATL cells and abnormal Polycomb-miRNA-signal transduction

基于ATL患者样本的综合数据集，我们解决了ATL的确切分子机制，这应该是临床治疗方案的目标。利用微阵列技术，我们确定了白血病细胞特异性基因表达模式。此外，我们发现p38和Hedgehog信号通路的激活支持促生存能力。我们对患者来源的原代ATL细胞进行了全局组蛋白甲基化分析。我们成功地在ATL细胞中检测到大量具有异常抑制H3K27me3标记的基因启动子。有趣的是，税收触发的永生化细胞部分模仿了在ATL细胞中观察到的甲基化模式。同时，我们发现NF-kB信号和EZH2之间存在密切关系。尽管在DLBCL中没有观察到EZH2活性突变，但EZH2抑制剂显著杀死了患者的ATL细胞。我们的研究结果表明，ATL具有依赖ezh2的稳健和全局表观遗传重排的特征。

Based on our comprehensive dataset from ATL patient samples, we addressed the exact molecular mechanism of ATL, which should be targeted in clinical regimens. Using a microarray technique, we identified leukemic cell-specific gene expression pattern. In addition, we revealed activation of p38 and Hedgehog signaling pathways, which supported pro-survival capability.We performed global histone methylation profiling of patient-derived primary ATL cells. We successfully detected the numerous gene promoters with aberrant repressive H3K27me3 mark in ATL cells. Interestingly, Tax-triggered immortalizing cells partially mimicked the methylation pattern observed in ATL cells. In parallel, we identified an intimate relationship between NF-kB signaling and EZH2. Despite the absence of EZH2 active mutation observed in DLBCL, EZH2 inhibitors significantly killed patient ATL cells. Our findings indicate that ATL is characterized by EZH2-dependent robust and global epigenetic rearrangement.