Zou Qin, Tan Shi, Yang Zailin, Zhan Qian, Jin Hongjun, Xian Jingrong, Zhang Shuaishuai, Yang Liyuan, Wang Lu, Zhang Ling
Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
Department of Clinical Laboratory, Chongqing Health Center for Women and Children, Chongqing, China.
Theranostics. 2017 Jun 1;7(8):2289-2304. doi: 10.7150/thno.19439. eCollection 2017.
Accumulating evidence has defined (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 . 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 mutations. This indicates an attractive therapeutic avenue for PML targeting and/or autophagy inhibition in the treatment of NPM1-mutated AML.
越来越多的证据表明，核仁磷酸蛋白1（NPM1）突变是急性髓系白血病（AML）中的一个驱动基因事件，而NPM1突变型AML的发病机制仍有待充分阐明。在本研究中，我们发现突变型NPM1提高了自噬活性，且自噬激活有助于白血病细胞存活。同时，我们还发现早幼粒细胞白血病基因（PML）在原发性NPM1突变的AML原始细胞和NPM1-mA阳性OCI-AML3细胞中高表达及其胞质移位。从机制上讲，突变型NPM1与PML相互作用并介导其去定位以及稳定化。值得注意的是，敲低NPM1-mA会损害自噬活性，而诱导PML表达则可逆转这种效应。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表达和自噬有利于由NPM1突变驱动的白血病转化。这表明在治疗NPM1突变型AML中，靶向PML和/或抑制自噬是一条有吸引力的治疗途径。
