Epigenetic silencing of microRNA-193a contributes to leukemogenesis in t(8;21) acute myeloid leukemia by activating the PTEN/PI3K signal pathway
Epigenetic silencing of microRNA-193a contributes to leukemogenesis in t(8;21) acute myeloid leukemia by activating the PTEN/PI3K signal pathway
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microRNA-193a 的表观遗传沉默通过激活 PTEN/PI3K 信号通路促进 t(8;21) 急性髓系白血病的白血病发生。
DOI：
10.1182/blood-2012-07-444729
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发表时间：
2013-01-17
期刊：
影响因子：
20.3
通讯作者：
Yu, Li
中科院分区：
文献类型：
--
作者：
Li, Yonghui;Gao, Li;Yu, Li
t（8; 21）是急性髓性白血病（AML）中最常见的染色体易位之一，被认为是白血病起始事件。与t（8;21）AML中表达的AML 1/ETO相关的microRNA失调的生物学和临床意义尚不清楚。在这里，我们发现AML 1/ETO通过结合AML 1结合位点和招募染色质重塑酶来触发microRNA-193 a（miR-193 a）的异染色质沉默。miR-193 a的抑制扩大了融合蛋白AML-ETO的致癌活性，因为miR-193 a直接抑制多个靶基因的表达，如AML 1/ETO、DNMT 3a、HDAC 3、KIT、CCND 1和MDM 2，并间接增加PTEN。提高miR-193 a水平可诱导G（1）阻滞、凋亡和恢复白血病细胞分化。我们的研究确定了miR-193 a和PTEN作为AML 1/ETO的靶点，并提供了将肿瘤抑制基因miR-193 a和PTEN的表观遗传沉默与髓样前体细胞分化阻滞联系起来的证据。我们的研究结果表明，涉及miR-193 a和AML 1/ETO/DNMT/HDAC的反馈回路，与PTEN/PI 3 K信号通路合作并有助于体外和体内白血病的发生，可以通过药物破坏AML 1/ETO/DNMT/HDAC复合物或增强t（8;21）-白血病中的miR-193 a成功靶向。
t(8;21) is one of the most frequent chromosomal translocations occurring in acute myeloid leukemia (AML) and is considered the leukemia-initiating event. The biologic and clinical significance of microRNA dysregulation associated with AML1/ETO expressed in t(8;21) AML is unknown. Here, we show that AML1/ETO triggers the heterochromatic silencing of microRNA-193a (miR-193a) by binding at AML1-binding sites and recruiting chromatin-remodeling enzymes. Suppression of miR-193a expands the oncogenic activity of the fusion protein AML-ETO, because miR-193a represses the expression of multiple target genes, such as AML1/ETO, DNMT3a, HDAC3, KIT, CCND1, and MDM2 directly, and increases PTEN indirectly. Enhanced miR-193a levels induce G(1) arrest, apoptosis, and restore leukemic cell differentiation. Our study identifies miR-193a and PTEN as targets for AML1/ETO and provides evidence that links the epigenetic silencing of tumor suppressor genes miR-193a and PTEN to differentiation block of myeloid precursors. Our results indicated a feedback circuitry involving miR-193a and AML1/ETO/DNMTs/HDACs, cooperating with the PTEN/PI3K signaling pathway and contributing to leukemogenesis in vitro and in vivo, which can be successfully targeted by pharmacologic disruption of the AML1/ETO/DNMTs/HDACs complex or enhancement of miR-193a in t(8;21)-leukemias.