Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637-1470, USA.
Semin Hematol. 2013 Jan;50(1):61-9. doi: 10.1053/j.seminhematol.2013.01.004.
The recent identification of covalent cytosine modifications derived from the metabolism of 5-methylcytosine (5-mC) and catalyzed by the TET proteins has facilitated molecular insight into a new subclass of acute myeloid leukemias (AMLs). TET2-mutant AMLs have the predicted hypermethylation phenotype expected given the inability of the mutant TET2 protein to convert 5-mC to 5-hydroxymethylcytosine (5-hmC). In addition, IDH1/2 mutations confer a gain-of-function, allowing the enzymes to process α-ketoglutarate to 2-hydroxyglutarate, which inhibits the TET proteins and ultimately induces the same hypermethylation phenotype. New techniques are being developed rapidly that have the unprecedented capacity to distinguish among the various covalent cytosine modifications now known to exist. Soon, these methods will be harnessed to yield a new level of insight into AMLs with altered distribution of 5-hmC, information that may allow new diagnostic and therapeutic approaches for patients with this subtype of AML.
最近，通过 TET 蛋白催化，对 5-甲基胞嘧啶（5-mC）代谢衍生的共价胞嘧啶修饰的鉴定，促进了对急性髓系白血病（AML）的一个新亚类的分子认识。TET2 突变型 AML 具有预期的高甲基化表型，因为突变型 TET2 蛋白无法将 5-mC 转化为 5-羟甲基胞嘧啶（5-hmC）。此外，IDH1/2 突变赋予了酶的功能获得，使酶能够将 α-酮戊二酸转化为 2-羟基戊二酸，从而抑制 TET 蛋白，最终诱导相同的高甲基化表型。新的技术正在迅速发展，具有空前的能力来区分现在已知存在的各种共价胞嘧啶修饰。很快，这些方法将被用来深入了解 AML 中 5-hmC 的分布改变，这些信息可能为患有这种 AML 亚型的患者提供新的诊断和治疗方法。
