Haematologica. 2013 Dec;98(12):1912-20. doi: 10.3324/haematol.2013.088740. Epub 2013 Jul 5.
The discovery that the Ten-Eleven Translocation (TET) hydroxylases cause DNA demethylation has fundamentally changed the notion of how DNA methylation is regulated. Clonal analysis of the hematopoetic stem cell compartment suggests that TET2 mutations can be early events in hematologic cancers and recent investigations have shown TET2 mutations in diffuse large B-cell lymphoma. However, the detection rates and the types of TET2 mutations vary, and the relation to global methylation patterns has not been investigated. Here, we show TET2 mutations in 12 of 100 diffuse large B-cell lymphomas with 7% carrying loss-of-function and 5% carrying missense mutations. Genome-wide methylation profiling using 450K Illumina arrays identified 315 differentially methylated genes between TET2 mutated and TET2 wild-type cases. TET2 mutations are primarily associated with hypermethylation within CpG islands (70%; P<0.0001), and at CpG-rich promoters (60%; P<0.0001) of genes involved in hematopoietic differentiation and cellular development. Hypermethylated loci in TET2 mutated samples overlap with the bivalent (H3K27me3/H3K4me3) silencing mark in human embryonic stem cells (P=1.5×10(-30)). Surprisingly, gene expression profiling showed that only 11% of the hypermethylated genes were down-regulated, among which there were several genes previously suggested to be tumor suppressors. A meta-analysis suggested that the 35 hypermethylated and down-regulated genes are associated with the activated B-cell-like type of diffuse large B-cell lymphoma in other studies. In conclusion, our data suggest that TET2 mutations may cause aberrant methylation mainly of genes involved in hematopoietic development, which are silenced but poised for activation in human embryonic stem cells.
TET 羟化酶导致 DNA 去甲基化的发现从根本上改变了人们对 DNA 甲基化如何调控的认识。造血干细胞区室的克隆分析表明，TET2 突变可能是血液恶性肿瘤的早期事件，最近的研究表明弥漫性大 B 细胞淋巴瘤存在 TET2 突变。然而，TET2 突变的检测率和类型存在差异，且与全基因组甲基化模式的关系尚未得到研究。在这里，我们在 100 例弥漫性大 B 细胞淋巴瘤中有 12 例发现 TET2 突变，其中 7%存在功能丧失性突变，5%存在错义突变。使用 450K Illumina 阵列进行全基因组甲基化谱分析，在 TET2 突变和 TET2 野生型病例之间鉴定出 315 个差异甲基化基因。TET2 突变主要与造血分化和细胞发育相关基因的 CpG 岛（70%；P<0.0001）和 CpG 丰富启动子（60%；P<0.0001）内的过度甲基化有关。TET2 突变样本中的高甲基化基因座与人类胚胎干细胞中的二价（H3K27me3/H3K4me3）沉默标记重叠（P=1.5×10(-30))。令人惊讶的是，基因表达谱分析表明，只有 11%的高甲基化基因下调，其中有几个基因之前被认为是肿瘤抑制基因。荟萃分析表明，在其他研究中，35 个高甲基化和下调基因与激活的 B 细胞样弥漫性大 B 细胞淋巴瘤有关。总之，我们的数据表明，TET2 突变可能导致主要涉及造血发育的基因异常甲基化，这些基因在人类胚胎干细胞中沉默但处于激活状态。
