While aberrant DNA methylation is a characteristic feature of tumor cells, our knowledge of how these DNA methylation patterns are established and maintained is limited. DNA methyltransferases and ten-eleven translocation methylcytosine dioxygenases (TETs) function has been found altered in a variety of cancer types. Here, we report that in T cell acute lymphoblastic leukemia (T-ALL) the MYC oncogene controls the expression of TET1 and TET2 to maintain 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) patterns, which is associated with tumor cell-specific gene expression. We found that cellular senescence and tumor regression upon MYC inactivation in T-ALL was associated with genome-wide changes in 5mC and 5hmC patterns. Correlating with the changes in DNA (hydroxy)methylation, we found that T-ALL overexpress TET1, while suppressing TET2 in a MYC-dependent fashion. Consequently, MYC inactivation led to an inverse expression pattern, decreasing TET1, while increasing TET2 levels. Knockdown of TET1 or ectopic expression of TET2 in T-ALL was associated with genome-wide changes in 5mC and 5hmC enrichment and decreased cell proliferation, suggesting a tumor promoting function of TET1, and a tumor suppressing role for TET2. Among the genes and pathways controlled by TET1, we found ribosomal biogenesis and translational control of protein synthesis highly enriched. Our finding that MYC directly deregulates the expression of TET1 and TET2 in T-ALL provides novel evidence that MYC controls DNA (hydroxy)methylation in a genome-wide fashion. It reveals a coordinated interplay between the components of the DNA (de)methylating machinery that contribute to MYC-driven tumor maintenance, highlighting the potential of specific TET enzymes for therapeutic strategies.

中文翻译：

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MYC 解除 TET1 和 TET2 表达的调控，以控制整体 DNA（羟基）甲基化和基因表达，以维持 T-ALL 中的肿瘤表型。

虽然异常的 DNA 甲基化是肿瘤细胞的一个特征，但我们对这些 DNA 甲基化模式如何建立和维持的了解是有限的。已发现 DNA 甲基转移酶和 10-11 易位甲基胞嘧啶双加氧酶 (TET) 功能在多种癌症类型中发生改变。在这里，我们报告说，在 T 细胞急性淋巴细胞白血病 (T-ALL) 中，MYC 癌基因控制 TET1 和 TET2 的表达以维持 5-甲基胞嘧啶 (5mC) 和 5-羟甲基胞嘧啶 (5hmC) 模式，这与肿瘤细胞相关特异性基因表达。我们发现 T-ALL 中 MYC 失活后的细胞衰老和肿瘤消退与 5mC 和 5hmC 模式的全基因组变化有关。与 DNA（羟基）甲基化的变化相关，我们发现 T-ALL 过表达 TET1，同时以依赖 MYC 的方式抑制 TET2。因此，MYC 失活导致反向表达模式，减少 TET1，同时增加 TET2 水平。T-ALL 中 TET1 的敲低或 TET2 的异位表达与 5mC 和 5hmC 富集的全基因组变化和细胞增殖降低有关，表明 TET1 的肿瘤促进功能和 TET2 的肿瘤抑制作用。在 TET1 控制的基因和通路中，我们发现核糖体生物发生和蛋白质合成的翻译控制高度丰富。我们发现 MYC 直接解除 T-ALL 中 TET1 和 TET2 的表达，提供了 MYC 以全基因组方式控制 DNA（羟基）甲基化的新证据。