Department of Cell Biology and Anatomy, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Curr Cancer Drug Targets. 2011 Sep;11(7):882-93. doi: 10.2174/156800911796798922.
Epigenetics play a critical role in controlling normal gene expression and altered epigenetics can lead to abnormal cellular differentiation, proliferation and survival. Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and is characterized by numerous epigenetic abnormalities. These epigenetic changes correspond to repressed activity of some genes and inappropriate activation of others. In contrast to genetic alterations stemming from mutations, deletions or translocation, epigenetic changes are relatively reversible when treated with certain small molecule-based anticancer agents. Histone deacetylase inhibitors (HDI) are a class of drugs capable of modifying the epigenetic status of ALL cells. Several recent preclinical and clinical studies have demonstrated the potential of HDI as therapeutic agents in ALL. This review summarizes recent studies on (1) the principles of epigenetics and their importance in ALL tumorigenesis; (2) the structure, mechanism of action and anti-tumor activity of HDI; (3) the first comprehensive summary of data from preclinical and clinical studies for HDI as the therapeutic agents for ALL; and (4) novel directions for future research on HDI and ALL.
表观遗传学在控制正常基因表达中起着关键作用，而表观遗传的改变可能导致细胞分化、增殖和存活的异常。急性淋巴细胞白血病（ALL）是儿童中最常见的恶性肿瘤，其特征是存在大量的表观遗传学异常。这些表观遗传学变化对应于某些基因的活性受到抑制和其他基因的异常激活。与源于突变、缺失或易位的遗传改变不同，当使用某些基于小分子的抗癌药物治疗时，表观遗传变化是相对可逆的。组蛋白去乙酰化酶抑制剂（HDI）是一类能够修饰 ALL 细胞表观遗传状态的药物。最近的一些临床前和临床研究表明，HDI 作为 ALL 的治疗剂具有潜在的应用价值。本文综述了（1）表观遗传学的原理及其在 ALL 肿瘤发生中的重要性；（2）HDI 的结构、作用机制和抗肿瘤活性；（3）HDI 作为 ALL 治疗剂的临床前和临床研究数据的首次全面总结；（4）HDI 与 ALL 未来研究的新方向。
