Cytosine methylation is a heritable epigenetic modification affecting gene transcription and the integrity of the genome. In human malignancies, aberrant DNA methylation is the most commonly observed epimutation, often manifested by promoter hypermethylation of tumor suppressor genes and hypomethylation of intergenic non-coding regions. The DNA methyltransferases (DNMTs) DNMT1, DNMT3A, and DNMT3B are the enzymes primarily responsible for methylation of CpG dinucleotides in mammalian DNA. Mutations in the coding sequence of DNMT3A are frequently found in human hematologic malignancies indicating that decreased DNMT3A activity may promote tumorigenesis in multiple hematopoietic lineages. Using targeted inactivation of Dnmt3a in mice Opavsky lab showed that Dnmt3a plays a tumor suppressor role in prevention of chronic B-cell lymphocytic leukemia, peripheral T cell lymphoma and myeloproliferative disease. Furthermore, Dnmt3b is a tumor suppressor gene in prevention of MYC-induced T cell lymphomas. Promoter hypomethylation accompanied by increased gene expression was found to be a frequent event in both mouse and human hematologic malignancies.
