Cabrero Monica, Wei Yue, Yang Hui, Ganan-Gomez Irene, Bohannan Zach, Colla Simona, Marchesini Matteo, Bravo Guillermo Montalban, Takahashi Koichi, Bueso-Ramos Carlos, Garcia-Manero Guillermo
Departments of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
Departments of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
Leuk Res. 2016 May;44:1-7. doi: 10.1016/j.leukres.2016.02.009. Epub 2016 Feb 26.
EZH2 genetic mutations are common in myelodysplastic syndrome (MDS), which implies that this gene has a pathophysiological role in the disease. To further characterize molecular alterations of EZH2, and their potential prognostic impact in MDS, we assessed EZH2 RNA expression in primary bone marrow CD34+ cells from 78 patients. We found that 47% of patients have reduced EZH2 expression compared to normal controls. Further analyses revealed that EZH2 is significantly underexpressed in patients bearing chromosome 7 or 7q deletions (7-alt) when compared to controls, diploid patients, and patients with other cytogenetic alterations (p<0.05). In survival analysis, we found a non-significant trend toward overall survival (OS) being better among patients with EZH2 underexpression (median OS 55 vs. 36 months; p=0.71). Importantly, this trend became significant when the analysis was restricted to the subset of cases without alterations in chromosome 7 (62 vs. 36 months; p=0.033). Furthermore, our previous work has identified a spectrum of innate immune genes in MDS CD34+ cells that are deregulated via abnormal promoter histone methylation. Because EZH2 is a key regulator of histone methylation, we assessed the relationship between deregulation of these genes and EZH2 underexpression. We observed that the mRNA levels of 11 immune genes were higher in the EZH2 underexpression group and that immune gene expression was significantly higher in patients with concomitant EZH2 underexpression and KDM6B (also known as JMJD3, an H3K27 demethylase) overexpression. Taken together, these data indicate that EZH2 underexpression may have unique impact on the molecular pathogenesis and prognosis in MDS and be an important marker for patients without chromosome 7 alteration.
EZH2基因突变在骨髓增生异常综合征（MDS）中很常见，这表明该基因在该疾病中具有病理生理作用。为了进一步表征EZH2的分子改变及其在MDS中的潜在预后影响，我们评估了78例患者原发性骨髓CD34+细胞中EZH2的RNA表达。我们发现，与正常对照相比，47%的患者EZH2表达降低。进一步分析显示，与对照、二倍体患者以及其他细胞遗传学改变的患者相比，携带7号染色体或7q缺失（7-alt）的患者中EZH2明显低表达（p<0.05）。在生存分析中，我们发现EZH2低表达的患者总生存期（OS）有更好的趋势，但无统计学意义（中位OS 55个月对36个月；p=0.71）。重要的是，当分析仅限于7号染色体无改变的病例子集时，这种趋势变得显著（62个月对36个月；p=0.033）。此外，我们之前的研究已经在MDS CD34+细胞中鉴定出一系列通过异常启动子组蛋白甲基化而失调的先天免疫基因。由于EZH2是组蛋白甲基化的关键调节因子，我们评估了这些基因失调与EZH2低表达之间的关系。我们观察到，EZH2低表达组中11个免疫基因的mRNA水平较高，并且在EZH2低表达与KDM6B（也称为JMJD3，一种H3K27去甲基化酶）过表达同时存在的患者中免疫基因表达显著更高。综上所述，这些数据表明EZH2低表达可能对MDS的分子发病机制和预后有独特影响，并且是7号染色体无改变患者的重要标志物。
