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目的探索表观遗传学机制对白血病细胞维甲酸受体β基因(RARβ)表达的调控作用及意义。方法应用 DNA 甲基化酶抑制剂地西他滨(DAC)和组蛋白去乙酰化酶抑制剂丙戊酸钠(VPA)与全反式维甲酸(ATRA)处理白血病细胞;RARβ基因甲基化测定和表达定量;染色质免疫沉淀。结果 56例急性髓系白血病(AML)患者 RARβ基因甲基化总阳性率为64.3%。DAC 与 VPA 可显著增加 ATRA 对 RARβ表达的激活作用。染色质免疫沉淀实验证明 DAC 和 VPA 通过 DNA 去甲基化和组蛋白乙酰化作用上调 RARβ表达。三药联合可诱导部分 U937细胞出现髓系分化标记 CD11b,使克隆形成能力明显下降。结论表观遗传学调控剂与 ATRA 联合应用可激活 RARβ的表达,具有协同抗白血病作用。
Objective To explore the regulatory effect of epigenetic mechanism on the expression of retinoic acid receptor β gene (leukemia cell RARβ) and its significance. Methods Leukemia cells were treated with DNA methylation inhibitor decitabine (DAC) and histone deacetylase inhibitors VPA and ATRA. Methylation of RARβ gene Determination and expression quantification; Chromatin immunoprecipitation. Results The total positive rate of RARβ gene methylation in 56 cases of acute myeloid leukemia (AML) was 64.3%. DAC and VPA significantly increased the activation of RARβ expression by ATRA. Chromatin immunoprecipitation experiments demonstrated that DAC and VPA upregulate RARβ expression through DNA demethylation and histone acetylation. Combination of three drugs can induce part of U937 cells appear myeloid differentiation marker CD11b, the clonality decreased significantly. Conclusion The combination of epigenetic regulators and ATRA can activate the expression of RARβ and has synergistic anti-leukemia effect.