Hyperthermia Selectively Destabilizes Oncogenic Fusion Proteins

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, includin...

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Published inBlood cancer discovery Vol. 2; no. 4; pp. 388 - 401
Main Authors Maimaitiyiming, Yasen, Wang, Qian Qian, Yang, Chang, Ogra, Yasumitsu, Lou, Yinjun, Smith, Clayton A, Hussain, Liaqat, Shao, Yi Ming, Lin, Jiebo, Liu, Jinfeng, Wang, Lingfang, Zhu, Yong, Lou, Haiyan, Huang, Yuan, Li, Xiaoxia, Chang, Kao-Jung, Chen, Hao, Li, Hongyan, Huang, Ying, Tse, Eric, Sun, Jie, Bu, Na, Chiou, Shih-Hwa, Zhang, Yan Fang, Hua, Hao Ying, Ma, Li Ya, Huang, Ping, Ge, Ming Hua, Cao, Feng-Lin, Cheng, Xiaodong, Sun, Hongzhe, Zhou, Jin, Vasliou, Vasilis, Xu, Pengfei, Jin, Jie, Bjorklund, Mikael, Zhu, Hong-Hu, Hsu, Chih-Hung, Naranmandura, Hua
Format Journal Article
LanguageEnglish
Published United States American Association for Cancer Research 01.07.2021
Subjects
Humans
Hyperthermia, Induced
Leukemia, Promyelocytic, Acute - drug therapy
Oncogene Proteins, Fusion - genetics
Tretinoin - therapeutic use
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Abstract 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 , 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. Hyperthermia destabilizes oncofusion proteins including PML/RARα and acts synergistically with standard arsenic therapy in relapsed and refractory APL. The results open up the possibility that heat shock sensitivity may be an easily targetable vulnerability of oncofusion-driven cancers. .
AbstractList Abstract 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. Significance: Hyperthermia destabilizes oncofusion proteins including PML/RARα and acts synergistically with standard arsenic therapy in relapsed and refractory APL. The results open up the possibility that heat shock sensitivity may be an easily targetable vulnerability of oncofusion-driven cancers. See related commentary by Wu et al., p. 300.
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 , 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. Hyperthermia destabilizes oncofusion proteins including PML/RARα and acts synergistically with standard arsenic therapy in relapsed and refractory APL. The results open up the possibility that heat shock sensitivity may be an easily targetable vulnerability of oncofusion-driven cancers. .
PML-RARα and other fusion oncoproteins are heat unstable, and prone to aggregation and degradation in hyperthermia. Proof-of-principle patient cases illustrate how this vulnerability may be potentially exploited for therapy of refractory acute promyelocytic leukemia. 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.
Author Liu, Jinfeng
Zhu, Hong-Hu
Hsu, Chih-Hung
Wang, Lingfang
Shao, Yi Ming
Li, Hongyan
Hussain, Liaqat
Li, Xiaoxia
Sun, Hongzhe
Ogra, Yasumitsu
Zhu, Yong
Chang, Kao-Jung
Ma, Li Ya
Maimaitiyiming, Yasen
Cheng, Xiaodong
Jin, Jie
Bjorklund, Mikael
Huang, Yuan
Huang, Ying
Hua, Hao Ying
Ge, Ming Hua
Bu, Na
Huang, Ping
Yang, Chang
Zhang, Yan Fang
Xu, Pengfei
Naranmandura, Hua
Tse, Eric
Sun, Jie
Cao, Feng-Lin
Wang, Qian Qian
Lou, Yinjun
Chiou, Shih-Hwa
Smith, Clayton A
Lou, Haiyan
Zhou, Jin
Vasliou, Vasilis
Chen, Hao
Lin, Jiebo
AuthorAffiliation 6 Blood Disorders and Cellular Therapies Center, University of Colorado Hospital, Denver, ­Colorado
4 Department of Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
7 Department of Pharmacology, Inner Mongolia Medical University, Hohhot, China
1 Department of Hematology of First Affiliated Hospital, and Department of Public Health, Zhejiang University School of Medicine, Hangzhou, China
12 Division of Newborn Medicine and Program in Epigenetics, Children's Hospital, Harvard Medical School, Boston, Massachusetts
10 Department of Hematology, the First Affiliated Hospital, Harbin Medical University, Harbin, China
11 Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan, China
3 Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, Hangzhou, China
14 Institute of Genetics, Zhejiang University, and Department of Genetics, School of Medicine, Zhejiang University, Hangzhou, China
15 Department of Medici
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Snippet 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,...
Abstract The PML/RARα fusion protein is the oncogenic driver in acute promyelocytic leukemia (APL). Although most APL cases are cured by PML/RARα-targeting...
PML-RARα and other fusion oncoproteins are heat unstable, and prone to aggregation and degradation in hyperthermia. Proof-of-principle patient cases illustrate...
SourceID pubmedcentral
crossref
pubmed
SourceType Open Access Repository
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Index Database
StartPage 388
SubjectTerms Humans
Hyperthermia, Induced
Leukemia, Promyelocytic, Acute - drug therapy
Oncogene Proteins, Fusion - genetics
Tretinoin - therapeutic use
Title Hyperthermia Selectively Destabilizes Oncogenic Fusion Proteins
URI https://www.ncbi.nlm.nih.gov/pubmed/34661159
https://pubmed.ncbi.nlm.nih.gov/PMC8513904
Volume 2
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