Bewersdorf Jan Philipp, Shallis Rory, Stahl Maximilian, Zeidan Amer M
Department of Internal Medicine, Section of Hematology, Yale University School of Medicine, New Haven, CT, USA.
Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Ther Adv Hematol. 2019 Jan 11;10:2040620718816698. doi: 10.1177/2040620718816698. eCollection 2019.
Epigenetics refers to the regulation of gene expression mainly by changes in DNA methylation and modifications of histone proteins without altering the actual DNA sequence. While epigenetic modifications are essential for normal cell differentiation, several driver mutations in leukemic pathogenesis have been identified in genes that affect epigenetic processes, such as DNA methylation and histone acetylation. Several therapeutic options to target epigenetic alterations in acute myeloid leukemia (AML) have been successfully tested in preclinical studies and various drugs have already been approved for use in clinical practice. Among these already approved therapeutics are hypomethylating agents (azacitidine and decitabine) and isocitrate dehydrogenase inhibitors (ivosidenib, enasidenib). Other agents such as bromodomain-containing epigenetic reader proteins and histone methylation (e.g. DOT1L) inhibitors are currently in advanced clinical testing. As several epigenetic therapies have only limited efficacy when used as single agents, combination therapies that target AML pathogenesis at different levels and exploit synergistic mechanisms are also in clinical trials. Combinations of either epigenetic therapies with conventional chemotherapy, different forms of epigenetic therapies, or epigenetic therapies with immunotherapy are showing promising early results. In this review we summarize the underlying pathophysiology and rationale for epigenetically-based combination therapies, review current preclinical and clinical data and discuss the future directions of epigenetic therapy combinations in AML.
表观遗传学是指主要通过DNA甲基化变化和组蛋白修饰来调控基因表达，而不改变实际的DNA序列。虽然表观遗传修饰对于正常细胞分化至关重要，但在影响表观遗传过程的基因（如DNA甲基化和组蛋白乙酰化）中，已经在白血病发病机制中鉴定出几种驱动突变。针对急性髓系白血病（AML）表观遗传改变的几种治疗选择已在临床前研究中成功测试，并且多种药物已被批准用于临床实践。这些已获批准的治疗药物包括去甲基化剂（阿扎胞苷和地西他滨）和异柠檬酸脱氢酶抑制剂（艾伏尼布、恩杂鲁胺）。其他药物，如含溴结构域的表观遗传读取蛋白和组蛋白甲基化（如DOT1L）抑制剂，目前正处于高级临床试验阶段。由于几种表观遗传疗法作为单一药物使用时疗效有限，针对AML发病机制不同水平并利用协同机制的联合疗法也在进行临床试验。表观遗传疗法与传统化疗、不同形式的表观遗传疗法或表观遗传疗法与免疫疗法的联合应用均显示出有希望的早期结果。在本综述中，我们总结了基于表观遗传学的联合疗法的潜在病理生理学和基本原理，回顾了当前的临床前和临床数据，并讨论了AML表观遗传疗法联合应用的未来方向。
