Lenalidomide-mediated enhanced translation of C/EBPα-p30 protein up-regulates expression of the antileukemic microRNA-181a in acute myeloid leukemia
Lenalidomide-mediated enhanced translation of C/EBPα-p30 protein up-regulates expression of the antileukemic microRNA-181a in acute myeloid leukemia
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DOI：
10.1182/blood-2012-05-428573
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发表时间：
2013-01-03
期刊：
影响因子：
20.3
通讯作者：
Marcucci, Guido
中科院分区：
文献类型：
--
作者：
Hickey, Christopher J.;Schwind, Sebastian;Marcucci, Guido
最近，我们发现miR-181a表达增加与细胞遗传学正常的急性髓性白血病（CN-AML）的预后改善相关。有趣的是，miR-181a表达在携带CEBPA突变的CN-AML患者中增加，CEBPA突变通常是双等位基因的，与更好的预后相关。CEBPA编码C/EBP α转录因子。我们在这里证明了N-末端CEBPA突变的存在和miR-181a的表达是相关的。事实上，截短的C/EBP α-p30同种型（其由N-末端突变CEBPA基因或由野生型CEBPA mRNA的差异翻译产生并且通常被认为不具有反式激活活性）结合miR-181a-1启动子并上调microRNA表达。此外，我们发现来那度胺，一种批准用于骨髓增生异常综合征和多发性骨髓瘤的药物，增强了C/EBP α-p30亚型的翻译，导致更高的miR-181a水平。在异种移植小鼠模型中，异位miR-181 a表达抑制肿瘤生长。类似地，来那度胺通过增加miR-181a表达而表现出抗肿瘤活性。这种调节途径可以解释AML患者亚群对诱导化疗的敏感性增加。总之，我们的数据为CEBPA突变的CN-AML患者中观察到的临床结局改善提供了潜在的解释，并表明来那度胺治疗提高C/EBP α-p30蛋白水平，进而提高miR-181 a可能使AML母细胞对化疗敏感。（血。2013; 121（1）：159 - 169）
Recently, we showed that increased miR-181a expression was associated with improved outcomes in cytogenetically normal acute myeloid leukemia (CN-AML). Interestingly, miR-181a expression was increased in CN-AML patients harboring CEBPA mutations, which are usually biallelic and associate with better prognosis. CEBPA encodes the C/EBP alpha transcription factor. We demonstrate here that the presence of N-terminal CEBPA mutations and miR-181a expression are linked. Indeed, the truncated C/EBP alpha-p30 isoform, which is produced from the N-terminal mutant CEBPA gene or from the differential translation of wild-type CEBPA mRNA and is commonly believed to have no transactivation activity, binds to the miR-181a-1 promoter and up-regulates the microRNA expression. Furthermore, we show that lenalidomide, a drug approved for myelodysplastic syndromes and multiple myeloma, enhances translation of the C/EBP alpha-p30 isoform, resulting in higher miR-181a levels. In xenograft mouse models, ectopic miR-181a expression inhibits tumor growth. Similarly, lenalidomide exhibits antitumorigenic activity paralleled by increased miR-181a expression. This regulatory pathway may explain an increased sensitivity to apoptosis-inducing chemotherapy in subsets of AML patients. Altogether, our data provide a potential explanation for the improved clinical outcomes observed in CEBPA-mutated CN-AML patients, and suggest that lenalidomide treatment enhancing the C/EBP alpha-p30 protein levels and in turn miR-181a may sensitize AML blasts to chemotherapy. (Blood. 2013; 121(1): 159-169)