Theranostics 2017; 7(8):2289-2304. doi:10.7150/thno.19439
NPM1 Mutant Mediated PML Delocalization and Stabilization Enhances Autophagy and Cell Survival in Leukemic Cells
1. Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing, China;
2. Department of Clinical Laboratory, Chongqing Health Center for Women and Children, Chongqing, China;
3. Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China;
4. The Center for Clinical Molecular Medical detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Zou Q, Tan S, Yang Z, Zhan Q, Jin H, Xian J, Zhang S, Yang L, Wang L, Zhang L. NPM1 Mutant Mediated PML Delocalization and Stabilization Enhances Autophagy and Cell Survival in Leukemic Cells. Theranostics 2017; 7(8):2289-2304. doi:10.7150/thno.19439. Available from http://www.thno.org/v07p2289.htm
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.
Keywords: acute myeloid leukemia, nucleophosmin 1, mutation, autophagy, cell survival, promyelocytic leukemia gene, AKT.