DNA methyltransferases (DNMTs) are an evolutionarily conserved family of DNA methylases, transferring a methyl group onto the fifth carbon of a cytosine residue. The mammalian DNMT family includes three major members that have functional methylation activities, termed DNMT1, DNMT3A, and DNMT3B. DNMT3A and DNMT3B are responsible for methylation establishment, whereas DNMT1 maintains methylation during DNA replication. Accumulating evidence demonstrates that regulation of DNA methylation by DNMTs is critical for normal hematopoiesis. Aberrant DNA methylation due to DNMT dysregulation and mutations is known as an important molecular event of hematological malignancies, such as DNMT3A mutations in acute myeloid leukemia. In this review, we first describe the basic methylation mechanisms of DNMTs and their functions in lymphocyte maturation and differentiation. We then discuss the current understanding of DNA methylation heterogeneity in leukemia and lymphoma to highlight the importance of studying DNA methylation targets. We also discuss DNMT mutations and pathogenic roles in human leukemia and lymphoma. We summarize the recent understanding of how DNMTs interact with transcription factors or cofactors to repress the expression of tumor suppressor genes. Finally, we highlight current clinical studies using DNMT inhibitors for the treatment of these hematological malignancies.

DNA 甲基转移酶 (DNMT) 是一个进化上保守的 DNA 甲基化酶家族，可将甲基转移到胞嘧啶残基的第五个碳上。哺乳动物 DNMT 家族包括三个具有功能性甲基化活性的主要成员，称为 DNMT1、DNMT3A 和 DNMT3B。 DNMT3A 和 DNMT3B 负责甲基化建立，而 DNMT1 在 DNA 复制过程中维持甲基化。越来越多的证据表明，DNMT 对 DNA 甲基化的调节对于正常造血至关重要。 DNMT 失调和突变导致的异常 DNA 甲基化被认为是血液恶性肿瘤的重要分子事件，例如急性髓系白血病中的 DNMT3A 突变。在这篇综述中，我们首先描述了 DNMT 的基本甲基化机制及其在淋巴细胞成熟和分化中的功能。然后我们讨论目前对白血病和淋巴瘤 DNA 甲基化异质性的理解，以强调研究 DNA 甲基化靶点的重要性。我们还讨论了 DNMT 突变及其在人类白血病和淋巴瘤中的致病作用。我们总结了最近对 DNMT 如何与转录因子或辅因子相互作用以抑制抑癌基因表达的理解。最后，我们重点介绍当前使用 DNMT 抑制剂治疗这些血液恶性肿瘤的临床研究。