Steinmetz Birgit, Hackl Hubert, Slabáková Eva, Schwarzinger Ilse, Smějová Monika, Spittler Andreas, Arbesu Itziar, Shehata Medhat, Souček Karel, Wieser Rotraud
a Department of Medicine I ; Medical University of Vienna ; Währinger Gürtel, Vienna , Austria.
Cell Cycle. 2014;13(18):2931-43. doi: 10.4161/15384101.2014.946869.
The product of the ecotropic virus integration site 1 (EVI1) gene, whose overexpression is associated with a poor prognosis in myeloid leukemias and some epithelial tumors, regulates gene transcription both through direct DNA binding and through modulation of the activity of other sequence specific transcription factors. Previous results from our laboratory have shown that EVI1 influenced transcription regulation in response to the myeloid differentiation inducing agent, all-trans retinoic acid (ATRA), in a dual manner: it enhanced ATRA induced transcription of the RARβ gene, but repressed the ATRA induction of the EVI1 gene itself. In the present study, we asked whether EVI1 would modulate the ATRA regulation of a larger number of genes, as well as biological responses to this agent, in human myeloid cells. U937 and HL-60 cells ectopically expressing EVI1 through retroviral transduction were subjected to microarray based gene expression analysis, and to assays measuring cellular proliferation, differentiation, and apoptosis. These experiments showed that EVI1 modulated the ATRA response of several dozens of genes, and in fact reinforced it in the vast majority of cases. A particularly strong synergy between EVI1 and ATRA was observed for GDF15, which codes for a member of the TGF-β superfamily of cytokines. In line with the gene expression results, EVI1 enhanced cell cycle arrest, differentiation, and apoptosis in response to ATRA, and knockdown of GDF15 counteracted some of these effects. The potential clinical implications of these findings are discussed.
嗜亲性病毒整合位点1（EVI1）基因的产物在髓系白血病和一些上皮肿瘤中过表达与预后不良相关，它通过直接结合DNA以及调节其他序列特异性转录因子的活性来调控基因转录。我们实验室之前的研究结果表明，EVI1以双重方式影响对髓系分化诱导剂全反式维甲酸（ATRA）的转录调控：它增强了ATRA诱导的RARβ基因转录，但抑制了EVI1基因本身的ATRA诱导。在本研究中，我们探究了EVI1是否会调节人类髓系细胞中更多基因的ATRA调控以及对该试剂的生物学反应。通过逆转录病毒转导异位表达EVI1的U937和HL-60细胞进行了基于微阵列的基因表达分析，并进行了测量细胞增殖、分化和凋亡的实验。这些实验表明，EVI1调节了几十个基因的ATRA反应，并且实际上在绝大多数情况下增强了该反应。对于编码细胞因子TGF-β超家族成员的GDF15，观察到EVI1与ATRA之间有特别强的协同作用。与基因表达结果一致，EVI1增强了对ATRA的细胞周期阻滞、分化和凋亡，并且敲低GDF15抵消了其中一些作用。讨论了这些发现的潜在临床意义。
