MGMT Expression Contributes to Temozolomide Resistance in H3K27M-Mutant Diffuse Midline Gliomas
MGMT Expression Contributes to Temozolomide Resistance in H3K27M-Mutant Diffuse Midline Gliomas
复制标题
DOI：
10.3389/fonc.2019.01568
复制
发表时间：
2020-01-21
影响因子：
4.7
通讯作者：
Fujii, Yukihiko
中科院分区：
文献类型：
--
作者：
Abe, Hideaki;Natsumeda, Manabu;Fujii, Yukihiko
弥漫性中线胶质瘤（DMG）对包括替莫唑胺（TMZ）在内的多种化疗药物表现出耐药性。DMG中的组蛋白基因突变触发表观遗传变化，包括DNA低甲基化，其中之一是经常缺乏O 6-甲基-鸟嘌呤-DNA甲基转移酶（MGMT）启动子甲基化，导致MGMT表达增加。我们从DMG患者中建立了具有HIST 1H 3 B K27 M和ACVR 1 G328 E基因突变的NGT 16细胞系，并使用该细胞系和其他具有H3 F3 A基因突变的DMG细胞系（SF 7761、SF 8628、JHH-DIPG 1）来分析MGMT启动子甲基化、MGMT蛋白表达和对TMZ的反应。4个DMG细胞系中的3个（NGT 16、SF 8628和JHH-DIPG 1）具有未甲基化的MGMT启动子，MGMT表达增加，并且显示出对TMZ处理的抗性。H3 F3 A基因突变的SF 7761细胞存在MGMT启动子甲基化，缺乏MGMT表达，对TMZ治疗敏感。NGT 16细胞系对ALK 2抑制剂K 02288的体外处理有反应。我们在体外证实，MGMT表达有助于DMG细胞系中的TMZ抗性。迫切需要开发治疗TMZ耐药DMG的新策略。
Diffuse midline gliomas (DMGs) show resistance to many chemotherapeutic agents including temozolomide (TMZ). Histone gene mutations in DMGs trigger epigenetic changes including DNA hypomethylation, one of which is a frequent lack of O6-methyl-guanine-DNA methyltransferase (MGMT) promoter methylation, resulting in increased MGMT expression. We established the NGT16 cell line with HIST1H3B K27M and ACVR1 G328E gene mutations from a DMG patient and used this cell line and other DMG cell lines with H3F3A gene mutation (SF7761, SF8628, JHH-DIPG1) to analyze MGMT promoter methylation, MGMT protein expression, and response to TMZ. Three out of 4 DMG cell lines (NGT16, SF8628, and JHH-DIPG1) had unmethylated MGMT promoter, increased MGMT expression, and showed resistance to TMZ treatment. SF7761 cells with H3F3A gene mutation showed MGMT promoter methylation, lacked MGMT expression, and sensitivity to TMZ treatment. NGT16 line showed response to ALK2 inhibitor K02288 treatment in vitro. We confirmed in vitro that MGMT expression contributes to TMZ resistance in DMG cell lines. There is an urgent need to develop new strategies to treat TMZ-resistant DMGs.