Hyperthermia Selectively Destabilizes Oncogenic Fusion Proteins

Yasen Maimaitiyiming, Qian Qian Wang, Chang Yang, Yasumitsu Ogra, Yinjun Lou, Clayton A. Smith, Liaqat Hussain, Yi Ming Shao, Jiebo Lin, Jinfeng Liu, Lingfang Wang, Yong Zhu, Haiyan Lou, Yuan Huang, Xiaoxia Li, Kao Jung Chang, Hao Chen, Hongyan Li, Ying Huang, Eric TseJie Sun, Na Bu, Shih Hwa Chiou, Yan Fang Zhang, Hao Ying Hua, Li Ya Ma, Ping Huang, Ming Hua Ge, Feng Lin Cao, Xiaodong Cheng, Hongzhe Sun, Jin Zhou, Vasilis Vasliou, Pengfei Xu, Jie Jin, Mikael Bjorklund, Hong Hu Zhu, Chih Hung Hsu*, Hua Naranmandura*

*此作品的通信作者

研究成果: Article同行評審

27 引文 斯高帕斯(Scopus)

摘要

The PML/RARα fusion protein is the oncogenic driver in acute promyelocytic leukemia (APL). Although 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 the 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 the SIAH2 E3 ligase. Hyperthermia and arsenic therapy destabilize PML/ RARα via distinct mechanisms and are synergistic in primary patient samples and in vivo, including three 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.

原文English
頁(從 - 到)388-401
頁數14
期刊Blood cancer discovery
2
發行號4
DOIs
出版狀態Published - 1 7月 2021

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