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.