MIR125B1 represses the degradation of the PML-RARA oncoprotein by an autophagy-lysosomal pathway in acute promyelocytic leukemia
MIR125B1 represses the degradation of the PML-RARA oncoprotein by an autophagy-lysosomal pathway in acute promyelocytic leukemia
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DOI：
10.4161/auto.29592
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发表时间：
2014-10-01
期刊：
影响因子：
13.3
通讯作者：
Chen, Yue-Qin
中科院分区：
文献类型：
--
作者：
Zeng, Cheng-Wu;Chen, Zhen-Hua;Chen, Yue-Qin
急性早幼粒细胞白血病（APL）的特征在于t（15;17）相关的PML-RARA融合基因。我们以前发现MIR 125 B1在APL患者中高表达，可能与疾病的发病机制有关;然而，MIR 125 B1发挥其致癌潜力的机制尚未完全阐明。在这里，我们证明了MIR 125 B1丰度与PML-RARA状态相关。MIR 125 B1过表达增强PML-RARA表达，抑制ATRA诱导的PML-RARA癌蛋白降解。RNA-seq分析揭示了PML-RARA降解途径与MIR 125 B1阻滞分化之间的直接联系。我们进一步证明MIR 125 B1介导的PML-RARA蛋白水解的阻断通过自噬-溶酶体途径调节，有助于抑制APL分化。此外，我们确定了DRAM 2（DNA损伤调节自噬调节剂2），自噬的关键调节剂，作为一种新的目标，至少部分负责自噬中涉及的MIR 125 B1的功能。重要的是，DRAM 2的敲低表型与过表达MIR 125 B1的作用相似，如PML-RARA降解受损、自噬抑制和骨髓细胞分化停滞。MIR 125 B1及其靶点DRAM 2的这些作用在APL小鼠模型中得到进一步证实。因此，MIR 125 B1失调可能通过自噬依赖性途径干扰ATRA介导的分化的有效性，代表了一种新的潜在APL治疗靶点。
Acute promyelocytic leukemia (APL) is characterized by the t(15;17)-associated PML-RARA fusion gene. We have previously found that MIR125B1 is highly expressed in patients with APL and may be associated with disease pathogenesis; however, the mechanism by which MIR125B1 exerts its oncogenic potential has not been fully elucidated. Here, we demonstrated that MIR125B1 abundance correlates with the PML-RARA status. MIR125B1 overexpression enhanced PML-RARA expression and inhibited the ATRA-induced degradation of the PML-RARA oncoprotein. RNA-seq analysis revealed a direct link between the PML-RARA degradation pathway and MIR125B1-arrested differentiation. We further demonstrated that the MIR125B1-mediated blockade of PML-RARA proteolysis was regulated via an autophagy-lysosomal pathway, contributing to the inhibition of APL differentiation. Furthermore, we identified DRAM2 (DNA-damage regulated autophagy modulator 2), a critical regulator of autophagy, as a novel target that was at least partly responsible for the function of MIR125B1 involved in autophagy. Importantly, the knockdown phenotypes for DRAM2 are similar to the effects of overexpressing MIR125B1 as impairment of PML-RARA degradation, inhibition of autophagy, and myeloid cell differentiation arrest. These effects of MIR125B1 and its target DRAM2 were further confirmed in an APL mouse model. Thus, MIR125B1 dysregulation may interfere with the effectiveness of ATRA-mediated differentiation through an autophagy-dependent pathway, representing a novel potential APL therapeutic target.