Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein
Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein
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DOI：
10.1016/j.ccr.2007.09.020
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发表时间：
2007-11-01
期刊：
影响因子：
50.3
通讯作者：
Nervi, Clara
中科院分区：
文献类型：
--
作者：
Fazi, Francesco;Racanicchi, Serena;Nervi, Clara
造血转录因子参与染色体易位，产生与白血病发病相关的融合蛋白。对患者原发白血病细胞的分析表明，那些携带t(8；21)产生AML1/ETO的患者显示出低水平的microRNA-223(miR-223)，该融合蛋白是最常见的急性髓系白血病相关融合蛋白，而microRNA-223是骨髓生成的调节因子。在这里，我们证明miR-223是AML1/ETO的直接转录靶点。通过在前miR-223基因的AML1结合部位招募染色质重塑酶，AML1/ETO诱导miR-223的异染色质沉默。异位miR-223表达、针对AML1/ETO的RNAi或去甲基化处理可增强miR-223水平并恢复细胞分化。在这里，我们确定了白血病融合蛋白的额外作用，将微小RNA基因座的表观遗传沉默与白血病的分化阻断联系起来。
Hematopoietic transcription factors are involved in chromosomal translocations, which generate fusion proteins contributing to leukemia pathogenesis. Analysis of patient's primary leukemia blasts revealed that those carrying the t(8;21) generating AML1/ETO, the most common acute myeloid leukemia-associated fusion protein, display low levels of a microRNA-223 (miR-223), a regulator of myelopoiesis. Here, we show that miR-223 is a direct transcriptional target of AML1/ETO. By recruiting chromatin remodeling enzymes at an AML1-binding site on the pre-miR-223 gene, AML1/ETO induces heterochromatic silencing of miR-223. Ectopic miR-223 expression, RNAi against AML1/ETO, or demethylating treatment enhances miR-223 levels and restores cell differentiation. Here, we identify an additional action for a leukemia fusion protein linking the epigenetic silencing of a microRNA locus to the differentiation block of leukemia.