Hyperthermia Selectively Destabilizes Fusion Oncoproteins

PML/RARα fusion protein is the oncogenic driver in acute promyelocytic leukemia (APL). While most APL cases are cured by PML/RARα targeting therapy, relapse and resistance can occur due to drug-resistant mutations. Here we report that thermal stress destabilizes PML/RARα protein, including clinically identified drug-resistant mutants. AML1/ETO and TEL/AML1 oncofusions show similar heat shock susceptibility. Mechanistically, mild hyperthermia stimulates aggregation of PML/RARα in complex with nuclear receptor corepressors leading to ubiquitin mediated degradation via SIAH2 E3 ligase. Hyperthermia and arsenic therapy destabilize P/R via distinct mechanisms and are synergistic in primary patient samples and in vivo including 3 refractory APL cases. Collectively, our results suggest that by taking advantage of a biophysical vulnerability of PML/RARα, thermal therapy may improve prognosis in drug-resistant or otherwise refractory APL. These findings serve as a paradigm for therapeutic targeting of fusion oncoprotein associated cancers by hyperthermia. Statement of Significance: Hyperthermia destabilizes oncofusion proteins including PML/RARα and acts synergistically with standard arsenic therapy in relapsed and refractory acute promyelocytic leukemia. The results open up the possibility that heat shock sensitivity may be an easily targetable vulnerability of oncofusion-driven cancers. for Cancer Research. by guest on May 20, 2021. Copyright 2021 American Association https://bloodcancerdiscov.aacrjournals.org Downloaded from