PML/RARα-Regulated miR-181a/b Cluster Targets the Tumor Suppressor RASSF1A in Acute Promyelocytic Leukemia.
PML/RARα-Regulated miR-181a/b Cluster Targets the Tumor Suppressor RASSF1A in Acute Promyelocytic Leukemia.
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DOI：
10.1158/0008-5472.can-14-3521
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发表时间：
2015-08-15
期刊：
影响因子：
11.2
通讯作者：
Behre G
中科院分区：
文献类型：
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作者：
Bräuer-Hartmann D;Hartmann JU;Wurm AA;Gerloff D;Katzerke C;Verga Falzacappa MV;Pelicci PG;Müller-Tidow C;Tenen DG;Niederwieser D;Behre G
在急性早幼粒细胞白血病（APL）中，全反式维甲酸（ATRA）治疗可诱导粒细胞成熟和白血病完全缓解。已知microRNA在白血病表型的形成中是关键的参与者。在这项研究中，我们报告了ATRA治疗后APL母细胞和NB 4白血病细胞中miR-181 a/B基因簇的下调作为药物反应的关键事件。我们发现，在细胞和转基因敲入小鼠中，PML/RARα癌基因激活了miR-181 a/B表达，APL患者标本中miR-181 a/B表达增强的证据证实并扩展了这一观察结果。RNAi介导的NB 4细胞中miR-181 a/B表达的减弱足以降低集落形成能力、增殖和存活。机制研究表明，miR-181 a/B通过直接结合ATRA调控的抑癌基因RASSF 1A的3′UTR而靶向该基因。miR-181 a/B的增强表达或RNAi介导的RASSF 1A衰减通过调节细胞周期调节因子cyclin D1抑制ATRA诱导的粒细胞分化。相反，RASSF 1A过表达增强细胞凋亡。最后，PML/RARα基因敲入小鼠和APL患者样本中的RASSF 1A水平降低。综上所述，我们的研究结果将miR-181 a和miR-181 b定义为PML/RARα相关APL中的oncomiR，并且它们揭示了RASSF 1A是APL中ATRA诱导的粒细胞分化程序的关键元件。
In acute promyelocytic leukemia (APL), all-trans-retinoic acid (ATRA) treatment induces granulocytic maturation and complete remission of leukemia. MicroRNAs are known to be critical players in the formation of the leukemic phenotype. In this study, we report downregulation of the miR-181a/b gene cluster in APL blasts and NB4 leukemia cells upon ATRA treatment as key event in the drug response. We found that miR-181a/b expression was activated by the PML/RARα oncogene in cells and transgenic knock-in mice, an observation confirmed and extended by evidence of enhanced expression of miR-181a/b in APL patient specimens. RNAi-mediated attenuation of miR-181a/b expression in NB4 cells was sufficient to reduce colony forming capacity, proliferation and survival. Mechanistic investigations revealed that miR-181a/b targets the ATRA-regulated tumor suppressor gene RASSF1A by direct binding to its 3′UTR. Enforced expression of miR-181a/b or RNAi-mediated attenuation of RASSF1A inhibited ATRA-induced granulocytic differentiation via regulation of the cell cycle regulator cyclin D1. Conversely, RASSF1A overexpression enhanced apoptosis. Lastly, RASSF1A levels were reduced in PML/RARα knock-in mice and APL patient samples. Taken together, our results define miR-181a and miR-181b as oncomiRs in PML/RARα-associated APL, and they reveal RASSF1A as a pivotal element in the granulocytic differentiation program induced by ATRA in APL.