title: DNA methyltransferases in hematologic malignancies.
abstract: DNA methyltransferases (DNMTs) are the key enzymes for genome methylation, which plays an important role in epigenetically regulated gene expression and repression. Mouse models with conditional knockout of the DNA methyltransferase 1 (DNMT1) and DNA methyltransferase 3A (DNMT3A) genes have revealed a role of DNA methylation in mediating the self-renewal and differentiation of normal hematopoietic stem cells (HSCs) and the leukemia stem cells (LSCs). Recently, various mutations of DNMT3A and other DNA methylation regulators have been identified in hematologic malignancies. Functional analysis of these mutations may lead to a better understanding of the disease mechanisms, and even the discovery of new biomarkers and/or drug targets, as well as more rational design of therapeutic regimens. Moreover, DNMTs inhibitors as epigenetic drugs have already been approved by US Food and Drug Administration for clinical use and some clinical trials are currently underway in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). This review focuses on the biology of DNMTs with regard to epigenetic regulation, HSC renewal/differentiation, and drug discovery for targeted therapy, and delineates the latest studies that have been conducted to unfold the relationship between aberrant DNMTs and hematologic malignancies.
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, China.
authors.forename: Keqin Kathy
authors.initials: KK
authors.lastname: Li
authors.forename: Liu-Fei
authors.initials: LF
authors.lastname: Luo
authors.forename: Yang
authors.initials: Y
authors.lastname: Shen
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.forename: Sai-Juan
authors.initials: SJ
authors.lastname: Chen
mesh_terms: D000818:Animals; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation / Q000187:drug effects*; D000090205:DNA Methyltransferase 3A; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D008958:Models, Molecular; D058990:Molecular Targeted Therapy / Q000379:methods; D009154:Mutation
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D004791:Enzyme Inhibitors; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A