期刊
THERANOSTICS
卷 7, 期 8, 页码 2289-2304出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.19439
关键词
acute myeloid leukemia; nucleophosmin 1; mutation; autophagy; cell survival; promyelocytic leukemia gene; AKT
资金
- National Natural Science Foundation of China [81271913]
- Graduate Fellowship in research innovation from the Chongqing Municipal Education Commission [CYS15134, CYS16140]
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.
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