Kobayashi Yukio
Hematology Division, National Cancer Center Hospital.
Rinsho Ketsueki. 2015 Oct;56(10):2015-23. doi: 10.11406/rinketsu.56.2015.
Cumulative evidence suggests that at least some hematologic malignancies are derived from alterations of epigenetic machinery. Next generation sequencing has revealed recurrent mutations of genes related to DNA methylation and histone modification in myelodysplastic syndromes (MDS), acute myeloid leukemia, malignant lymphoma, and multiple myeloma. Both these pathways are targetable and specific inhibitors of their related proteins are currently in development. Among these novel therapies, hypomethylating agents have been approved for MDS, and recently, histone deacetylase inhibitors became available for T-cell lymphoma and multiple myeloma. Agents currently undergoing clinical trials include inhibitors of IDH2 targeting DNA methylation, and EZH2, Dot1L, and BRD4 inhibitors designed to target either writers or readers of post-translational modifications (PTMs) of histones. In a phase I setting, where the maximum tolerated dose has not been reached, efficacy was reported with these agents. Furthermore, Dot1bL and IDH2 inhibitors have been shown to induce differentiation of leukemic blasts in patients with MLL gene rearrangements and IDH2 mutations, respectively, thus providing functional evidence supporting the use of inhibitors of epigenetic mechanisms as a means of differentiation therapy for hematologic malignancies.
越来越多的证据表明，至少某些血液系统恶性肿瘤源自表观遗传机制的改变。新一代测序技术已揭示了骨髓增生异常综合征（MDS）、急性髓系白血病、恶性淋巴瘤和多发性骨髓瘤中与DNA甲基化和组蛋白修饰相关基因的反复突变。这两条途径都是可靶向的，目前正在研发其相关蛋白的特异性抑制剂。在这些新型疗法中，去甲基化药物已被批准用于治疗MDS，最近，组蛋白脱乙酰酶抑制剂也已用于治疗T细胞淋巴瘤和多发性骨髓瘤。目前正在进行临床试验的药物包括靶向DNA甲基化的IDH2抑制剂，以及旨在靶向组蛋白翻译后修饰（PTM）的写入器或读取器的EZH2、Dot1L和BRD4抑制剂。在尚未达到最大耐受剂量的I期试验中，已报道了这些药物的疗效。此外，Dot1bL和IDH2抑制剂已分别被证明可诱导MLL基因重排患者和IDH2突变患者的白血病原始细胞分化，从而提供了功能证据，支持使用表观遗传机制抑制剂作为血液系统恶性肿瘤的分化治疗手段。
