PML-RARA A216V

Acute promyelocytic leukemia (APL) is characterized by the fusion gene promyelocytic leukemia-retinoic acid receptor-alpha (PML-RARA) and is conventionally treated with arsenic trioxide (ATO)...In addition, these mutations disrupt several hydrogen bonds, including interactions involving C212, C213 and C215, which are essential for ATO binding. The local and global structural features induced by these mutations provide mechanistic insight into ATO resistance and APL pathogenesis.

Immunoblotting confirmed that ATO-resistant cells were unable to undergo apoptosis as levels of pro-apoptotic (cleaved caspase-3, cleaved-PARP, BAX), anti-apoptotic (Bcl2, Bcl-xL, XIAP), and PML-RARA proteins remain unchanged in ATO-resistant cells except for downregulation of Bcl2 and upregulation of cleaved caspase-3 in UF1 following ATO/ATRA treatment. Our results indicate that venetoclax+ATO cooperates in inducing apoptosis of ATO-resistant cells through mitochondrial stress-induced ROS production coupled with PML-RARA degradation.