Mutation in the Unrearranged Allele Confers Resistance to Arsenic Trioxide in Acute Promyelocytic Leukemia.

Arsenic trioxide (ATO) is able to selectively target and degrade the disease-causing PML::RARα (P/R) oncoprotein in acute promyelocytic leukemia (APL) for curing the disease. However, some relapsed patients develop resistance to ATO due to mutations in the promyelocytic leukemia (PML) part of the fusion gene. A relapsed APL patient had shown resistance to ATO and chemotherapy and was identified to harbor a point mutation (A216V) in the unrearranged allele rather than the fusion gene. Here, we report that mutations in the unrearranged allele impede the ATO-induced destabilization and degradation of the wild-type P/R oncoprotein. Deletion of the coiled-coil domain in a PML mutant completely reversed wild-type P/R protein resistance to ATO by abolishing the interaction between PML and P/R proteins. Collectively, our findings reveal that a point mutation in the unrearranged allele can confer ATO resistance through a protein-protein interaction. Therefore, the unrearranged allele should also be screened for drug-resistant mutations in relapsed APL patients.