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NPM1 Mutant Mediated PML Delocalization and Stabilization Enhances Autophagy and Cell Survival in Leukemic Cells
Theranostics ( IF 12.4 ) Pub Date : 2017-06-01 , DOI: 10.7150/thno.19439
Qin Zou , Shi Tan , Zailin Yang , Qian Zhan , Hongjun Jin , Jingrong Xian , Shuaishuai Zhang , Liyuan Yang , Lu Wang , Ling Zhang

Accumulating evidence has defined nucleophosmin 1 (NPM1) mutation as a driver genetic event in acute myeloid leukemia (AML), whereas the pathogenesis of NPM1-mutated AML remains to be fully elucidated. In this study, we showed that mutant NPM1 elevated autophagic activity and autophagic activation contributed to leukemic cell survival in vitro. Meanwhile, we also found high expression of promyelocytic leukemia gene (PML) and its cytoplasmic dislocation in primary NPM1-mutated AML blasts and NPM1-mA positive OCI-AML3 cells. Mechanically, mutant NPM1 interacted with PML and mediated it delocalization as well as stabilization. Notably, NPM1-mA knockdown impaired autophagic activity, while induced expression of PML reversed this effect. Finally, we confirmed that PML modulated autophagic activity via AKT signal. These findings suggest that aberrant PML expression and autophagy are beneficial to the leukemic transformation driven by NPM1 mutations. This indicates an attractive therapeutic avenue for PML targeting and/or autophagy inhibition in the treatment of NPM1-mutated AML.

中文翻译:

NPM1突变体介导的PML脱域和稳定化增强白血病细胞中的自噬和细胞存活。

越来越多的证据将磷蛋白1(NPM1)突变定义为急性髓细胞性白血病(AML)的驱动基因事件,而NPM1突变的AML的发病机理仍有待充分阐明。在这项研究中,我们表明突变NPM1升高自噬活性和自噬激活有助于体外白血病细胞存活。同时,我们还在原NPM1突变的AML原始细胞和NPM1-mA阳性的OCI-AML3细胞中发现了早幼粒细胞白血病基因(PML)的高表达及其胞质脱位。在机械上,突变NPM1与PML相互作用并介导它的离域化和稳定化。值得注意的是,NPM1-mA敲低会损害自噬活性,而诱导表达的PML则逆转了这种作用。最后,我们证实PML通过AKT信号调节自噬活性。这些发现表明异常的PML表达和自噬对NPM1突变驱动的白血病转化是有益的。这表明在NPM1突变AML的治疗中PML靶向和/或自噬抑制的有吸引力的治疗途径。
更新日期:2017-08-02
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