Critical Role of c-Myc in Acute Myeloid Leukemia Involving Direct Regulation of miR-26a and Histone Methyltransferase EZH2.
Critical Role of c-Myc in Acute Myeloid Leukemia Involving Direct Regulation of miR-26a and Histone Methyltransferase EZH2.
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DOI：
10.1177/1947601911416357
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发表时间：
2011-05-01
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影响因子：
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通讯作者：
Fatica, Alessandro
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文献类型：
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作者：
Salvatori, Beatrice;Iosue, Ilaria;Fatica, Alessandro
c-Myc的表达增加或异常激活在白血病发生中起重要作用。在这里，我们表明，在急性髓系白血病（AML），c-Myc直接控制EZH 2，Polycomb抑制复合物2的组成部分，和miR-26 a的表达。miR-26 a在来自AML患者的原代母细胞中下调，并且在AML细胞的髓样分化期间，与c-Myc和Ezh 2水平的降低一起被诱导。以前，EZH 2在淋巴瘤中被证明在翻译水平上受miR-26 a调节。然而，我们证明在AML中，EZH 2的变异主要取决于c-Myc的转录控制。我们还发现，AML细胞中miR-26 a的强制表达能够通过下调细胞周期蛋白E2的表达来抑制细胞周期进程。此外，miR-26 a水平的增加增强了1，25-二羟维生素D（3）（VitD）的抗增殖作用，并刺激骨髓分化。我们的研究结果确定了AML中c-Myc的新分子靶点，并强调了miR-26 a作为白血病治疗靶点的吸引力。
Increased expression or aberrant activation of c-Myc plays an important role in leukemogenesis. Here, we show that in acute myeloid leukemia (AML), c-Myc directly controls the expression of EZH2, a component of the Polycomb repressive complex 2, and miR-26a. miR-26a is downregulated in primary blasts from AML patients and, during myeloid differentiation of AML cells, is induced together with a decrease in c-Myc and Ezh2 levels. Previously, EZH2 was shown to be regulated by miR-26a at the translational levels in lymphomas. However, we demonstrate that in AML, the variation of EZH2 mainly depends on c-Myc transcriptional control. We also show that enforced expression of miR-26a in AML cells is able to inhibit cell cycle progression by downregulating cyclin E2 expression. In addition, increased levels of miR-26a potentiate the antiproliferative effects of 1,25-dihydroxyvitamin D(3) (VitD) and stimulate myeloid differentiation. Our results identify new molecular targets of c-Myc in AML and highlight miR-26a attractiveness as a therapeutic target in leukemia.