Oki Yasuhiro, Issa Jean-Pierre J
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Cancer Treat Res. 2010;145:19-40. doi: 10.1007/978-0-387-69259-3_2.
Epigenetics refers to a stable, mitotically perpetuated regulatory mechanism of gene expression without an alteration of the coding sequence. Epigenetic mechanism include DNA methylation and histone tail modifications. Epigenetic regulation is part of physiologic development and becomes abnormal in neoplasia, where silencing of critical genes by DNA methylation or histone deacetylation can contribute to leukemogenesis as an alternative to deletion or loss-of-function mutation. In acute myelogenous leukemia (AML), aberrant DNA methylation can be observed in multiple functionally relevant genes such as p15, p 73, E-cadherin, ID 4, RARbeta2. Abnormal activities of histone tail-modifying enzymes have also been seen in AML, frequently as a direct result of chromosomal translocations. It is now clear that these epigenetic changes play a significant role in development and progression of AML, and thus constitute important targets of therapy. The aim of targeting epigenetic effector protein or "epigenetic therapy" is to reverse epigenetic silencing and reactive various genes to induce a therapeutic effect such as differentiation, growth arrest, or apoptosis. Recent clinical studies have shown the relative safety and efficacy of such epigenetic therapies.
表观遗传学是指一种稳定的、可通过有丝分裂延续的基因表达调控机制，且不改变编码序列。表观遗传机制包括DNA甲基化和组蛋白尾部修饰。表观遗传调控是生理发育的一部分，在肿瘤形成过程中会变得异常，其中通过DNA甲基化或组蛋白去乙酰化使关键基因沉默可作为缺失或功能丧失性突变的替代机制，从而促进白血病的发生。在急性髓性白血病（AML）中，可在多个功能相关基因如p15、p73、E-钙黏蛋白、ID4、RARβ2中观察到异常的DNA甲基化。在AML中也发现了组蛋白尾部修饰酶的异常活性，这通常是染色体易位的直接结果。现在很清楚，这些表观遗传变化在AML的发生和发展中起重要作用，因此构成了重要的治疗靶点。靶向表观遗传效应蛋白或“表观遗传治疗”的目的是逆转表观遗传沉默并激活各种基因，以诱导如分化、生长停滞或凋亡等治疗效果。最近的临床研究表明了这种表观遗传治疗的相对安全性和有效性。
