UTX/KDM6A Loss Enhances the Malignant Phenotype of Multiple Myeloma and Sensitizes Cells to EZH2 inhibition.
UTX/KDM6A Loss Enhances the Malignant Phenotype of Multiple Myeloma and Sensitizes Cells to EZH2 inhibition.
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DOI：
10.1016/j.celrep.2017.09.078
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发表时间：
2017-10-17
期刊：
影响因子：
8.8
通讯作者：
Licht JD
中科院分区：
文献类型：
--
作者：
Ezponda T;Dupéré-Richer D;Will CM;Small EC;Varghese N;Patel T;Nabet B;Popovic R;Oyer J;Bulic M;Zheng Y;Huang X;Shah MY;Maji S;Riva A;Occhionorelli M;Tonon G;Kelleher N;Keats J;Licht JD
组蛋白H3 K27去甲基化酶UTX的丢失或失活发生在几种恶性肿瘤中，包括多发性骨髓瘤（MM）。使用同基因细胞系统，我们发现UTX的丢失导致基因表达失活，最终促进MM细胞的增殖、克隆形成、粘附和致瘤性。此外，UTX突变细胞显示出对EZH 2（一种产生H3 K27 me 3的组蛋白甲基转移酶）抑制的体外和体内敏感性增加。这种敏感性与IRF 4和c-MYC水平的降低以及生发中心B细胞特有的IRF 4阻遏物如BCL 6和IRF 1的活化有关。通过EZH 2抑制剂在特定基因处重新平衡H3 K27 me 3水平可能是携带UTX突变的MM病例的治疗策略。Ezponda等人现在证明了UTX/KDM 6A（一种调节染色质的因子）的缺失如何导致多发性骨髓瘤，从而赋予这些细胞恶性特性。此外，他们显示了目前在临床试验中使用EZH 2抑制剂如何特别影响携带UTX损失的MM细胞。
Loss or inactivation of the histone H3K27 demethylase UTX occurs in several malignancies, including multiple myeloma (MM). Using an isogenic cell system, we found that loss of UTX leads to deactivation of gene expression ultimately promoting the proliferation, clonogenicity, adhesion and tumorigenicity of MM cells. Moreover, UTX-mutant cells showed increased in vitro and in vivo sensitivity to inhibition of EZH2, a histone methyltransferase that generates H3K27me3. Such sensitivity was related to a decrease in the levels of IRF4 and c-MYC, and an activation of repressors of IRF4 characteristic of germinal center B cells such as BCL6 and IRF1. Rebalance of H3K27me3 levels at specific genes through EZH2 inhibitors may be a therapeutic strategy in MM cases harboring UTX mutations. Ezponda et al. now demonstrate how the loss of UTX/KDM6A, a factor that regulates chromatin, contributes to multiple myeloma, conferring malignant properties to these cells. Moreover, they show how the use of EZH2 inhibitors, currently in clinical trials, specifically affect MM cells harboring UTX loss.
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