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Epigenetic Silencing of eyes absent 4 Gene by Acute Myeloid Leukemia 1-Eight-twenty-one Oncoprotein Contributes to Leukemogenesis in t（8;21） Acute Myeloid Leukemia

引用

Chinese Medical Journal 2016年第11期129卷 1355-1362页

作者： Sai Huang Meng-Meng Jiang Guo-Feng Chen Kun Qian Hong-Hao Gao Wei Guan Jin-Long Shi An-Qi Liu Jing Liu Bian-Hong Wang Yong-Hui Li Li Yu Department of Hematology Chinese PLA General Hospital Beijing 100853 China State Key Laboratory of Cancer Biology First Hospital Affiliated to The Fourth Military Medical University Xi'an Shaanxi 710032 China

Background： The acute myeloid leukemia 1 （AML1）-eight-twenty-one （ETO） fusion protein generated by the t（8;2 1）（q22;q22） translocation is considered to display a crucial role in leukemogenesis in AML. By focusing on the anti-leukemia effects of eyes absent 4 （EYA4） gene on AML cells, we investigated the biologic and molecular mechanism associated with AML 1 -ETO expressed in t（8;21） AML. Methods： Qualitative polymerase chain reaction （PCR）, quantitative reverse transcription PCR （RT-PCR）, and Western blotting analysis were used to observe the mRNA and protein expression levels of EYA4 in cell lines. Different plasmids （including mutant plasmids） of dual luciferase reporter vector were built to study the binding status of AML1-ETO to the promoter region of EYA4. Chromatin immunoprecipitation assay was used to study the epigenetic silencing mechanism of EYA4. Bisulfite sequencing was applied to detect the methylation status in EYA4 promoter region. The influence ofEYA4 gene in the cell proliferation, apoptosis, and cell clone-forming ability was detected by the technique of Cell Counting Kit-8, flow cytometry, and clonogenic assay. Results： EYA4 gene was hyperrnethylated in AMLI-ETO＋ patients and its expression was down-regulated by 6-fold in Kasumi-1 and SKNO-1 cells, compared to HL-60 and SKNO-1-siA/E cells, respectively. We demonstrated that AML1-ETO triggered the epigenetic silencing of EYA 4 gene by binding at AML 1-binding sites and recruiting histone deacetylase 1 and DNA methyltransferases. Enhanced EYA4 expression levels inhibited cellular proliferation and suppressed cell colony formation in AMLI-ETO cell lines. We also found EYA4 transfection increased apoptosis of Kasumi- 1 and SKNO-1 cells by 1.6-fold and 1.4-fold compared to negative control, respectively. Conclusions： Our study identified EYA4 gene as targets for AML1-ETO and indicated it as a novel tumor suppressor gene. In addition, we provided evidence that EYA4 gene might be a novel therapeutic targ

关键词： Acute Myeloid Gene 1-Eight-twenty-one Acute Myeloid Leukemia Epigenetics eyes absent 4

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