Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Division of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, FL 2033, USA.
Cell Rep. 2017 Oct 17;21(3):628-640. doi: 10.1016/j.celrep.2017.09.078.
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.
组蛋白 H3K27 去甲基酶 UTX 的缺失或失活发生在多种恶性肿瘤中，包括多发性骨髓瘤（MM）。使用同基因细胞系统，我们发现 UTX 的缺失会导致基因表达失活，最终促进 MM 细胞的增殖、集落形成、黏附和致瘤性。此外，UTX 突变细胞对 EZH2 抑制剂的体外和体内敏感性增加，EZH2 是一种生成 H3K27me3 的组蛋白甲基转移酶。这种敏感性与 IRF4 和 c-MYC 水平降低以及生发中心 B 细胞特征性的 IRF4 抑制物 BCL6 和 IRF1 的激活有关。通过 EZH2 抑制剂在特定基因上重新平衡 H3K27me3 水平可能是携带 UTX 突变的 MM 病例的一种治疗策略。
