Epigenetic modification as a therapeutic approach for B-cell lymphoma
Epigenetic modification as a therapeutic approach for B-cell lymphoma
复制标题
表观遗传修饰作为 B 细胞淋巴瘤的治疗方法
DOI：
10.11406/rinketsu.63.313
复制
发表时间：
2022
期刊：
影响因子：
--
通讯作者：
髙折 晃史
中科院分区：
文献类型：
--
作者：
錦織 桃子;髙折 晃史
调节免疫活性的基因在B细胞的生发中心反应期间被表观遗传修饰暂时抑制，并且当B细胞离开生发中心时被重新激活。EZH 2和其他表观遗传修饰基因的突变经常参与滤泡性淋巴瘤的发病机制，并导致退出生发中心所必需的基因沉默。Tazemetostat是一种EZH 2抑制剂，已在日本被批准用于治疗具有EZH 2功能获得性突变的滤泡性淋巴瘤。Tazemetostat恢复淋巴瘤细胞中MHC和CD 58的表达，并协同增强T细胞和自然杀伤细胞对淋巴瘤细胞的免疫反应。Tazemetostat还诱导淋巴瘤细胞分泌CCL 17/TARC并增强T细胞迁移。已知CD 58和CCL 17在霍奇金淋巴瘤的富含T细胞的肿瘤微环境的形成中发挥中心作用。我们发现tazemetostat增强了霍奇金/里德-斯滕伯格细胞中过表达基因的表达。表观遗传修饰剂和新的分子靶向治疗有望为淋巴瘤的发病机制和决定淋巴瘤组织学的机制提供新的见解。
Genes that regulate immunological activities are transiently suppressed by epigenetic modification during the germinal center reaction of B cells and reactivated when B cells exit the germinal center. Mutations of EZH2 and other epigenetic modifier genes are frequently involved in the pathogenesis of follicular lymphoma and lead to silencing of the genes necessary for exiting the germinal center. Tazemetostat, an EZH2 inhibitor, has been approved for the treatment of follicular lymphoma with EZH2 gain-of-function mutations in Japan. Tazemetostat restores the expressions of MHC and CD58 in lymphoma cells and synergistically enhances the immune reactions of T and natural killer cells against lymphoma cells. Tazemetostat also induces lymphoma cells to secrete CCL17/TARC and enhances T-cell migration. CD58 and CCL17 are known to play central roles in the formation of T-cell-rich tumor microenvironment of Hodgkin lymphoma. We found that tazemetostat enhances the expression of genes overexpressed in Hodgkin/Reed-Sternberg cells. Epigenetic modifiers and new molecular targeted therapies are expected to provide new insights into the pathogenesis of lymphoma and mechanisms determining the histology of lymphoma.