DNA methyltransferase inhibitors (DNMTi), most commonly cytidine analogs, are compounds that decrease 5'-cytosine methylation. DNMTi are used clinically based on the hypothesis that cytosine demethylation will lead to re-expression of tumor suppressor genes. 5-Aza-4'-thio-2'-deoxycytidine (Aza-TdCyd or ATC) is a recently described thiol-substituted DNMTi that has been shown to have anti-tumor activity in solid tumor models. In this study, we investigated the therapeutic potential of ATC in a murine transplantation model of myelodysplastic syndrome. ATC treatment led to the transformation of transplanted wild-type bone marrow nucleated cells into lymphoid leukemia, and healthy mice treated with ATC also developed lymphoid leukemia. Whole-exome sequencing revealed 1,000 acquired mutations, almost all of which were C>G transversions in a specific 5'-NCG-3' context. These mutations involved dozens of genes involved in human lymphoid leukemia, such as Notch1, Pten, Pax5, Trp53, and Nf1. Human cells treated in vitro with ATC showed 1,000 acquired C>G transversions in a similar context. Deletion of Dck, the rate-limiting enzyme for the cytidine salvage pathway, eliminated C>G transversions. Taken together, these findings demonstrate a highly penetrant mutagenic and leukemogenic phenotype associated with ATC. Significance: Treatment with a DNA methyltransferase inhibitor generates a distinct mutation signature and triggers leukemic transformation, which has important implications for the research and clinical applications of these inhibitors.

中文翻译：

---

DNA 甲基转移酶抑制剂 5-Aza-4'-thio-2'-Deoxycytidine 诱导 C>G 颠换和急性淋巴细胞白血病的发展。


DNA 甲基转移酶抑制剂 (DNMTi) 最常见的是胞苷类似物，是降低 5'-胞嘧啶甲基化的化合物。 DNMTi在临床上的使用是基于胞嘧啶去甲基化会导致抑癌基因重新表达的假设。 5-Aza-4'-thio-2'-deoxycytidine（Aza-TdCyd 或 ATC）是最近描述的硫醇取代的 DNMTi，已在实体瘤模型中显示出具有抗肿瘤活性。在这项研究中，我们研究了 ATC 在骨髓增生异常综合征小鼠移植模型中的治疗潜力。 ATC治疗导致移植的野生型骨髓有核细胞转化为淋巴白血病，接受ATC治疗的健康小鼠也患上淋巴白血病。全外显子组测序揭示了 1,000 个获得性突变，几乎所有突变都是特定 5'-NCG-3' 背景下的 C>G 颠换。这些突变涉及数十个与人类淋巴细胞白血病有关的基因，例如Notch1、Pten、Pax5、Trp53和Nf1。在体外用 ATC 处理的人类细胞在类似情况下显示出 1,000 次获得性 C>G 颠换。 Dck（胞苷挽救途径的限速酶）的缺失消除了 C>G 颠换。总而言之，这些发现证明了与 ATC 相关的高度渗透性致突变和致白血病表型。意义：使用 DNA 甲基转移酶抑制剂治疗会产生独特的突变特征并引发白血病转化，这对这些抑制剂的研究和临床应用具有重要意义。