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 Tse; Jie 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

doi:10.1158/2643-3230.BCD-20-0188

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

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.

Original language	English
Pages (from-to)	388-401
Number of pages	14
Journal	Blood cancer discovery
Volume	2
Issue number	4
DOIs	https://doi.org/10.1158/2643-3230.BCD-20-0188
State	Published - 1 Jul 2021

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10.1158/2643-3230.BCD-20-0188

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Maimaitiyiming, Y., Wang, Q. Q., Yang, C., Ogra, Y., Lou, Y., Smith, C. A., Hussain, L., Shao, Y. M., Lin, J., Liu, J., Wang, L., Zhu, Y., Lou, H., Huang, Y., Li, X., Chang, K. J., Chen, H., Li, H., Huang, Y., ... Naranmandura, H. (2021). Hyperthermia Selectively Destabilizes Oncogenic Fusion Proteins. Blood cancer discovery, 2(4), 388-401. https://doi.org/10.1158/2643-3230.BCD-20-0188

@article{b507e497b3d144f5b70b9620ac8fa03c,

title = "Hyperthermia Selectively Destabilizes Oncogenic Fusion Proteins",

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.",

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

note = "Publisher Copyright: {\textcopyright}2021 American Association for Cancer Research.",

year = "2021",

month = jul,

day = "1",

doi = "10.1158/2643-3230.BCD-20-0188",

language = "English",

volume = "2",

pages = "388--401",

journal = "Blood cancer discovery",

issn = "2643-3230",

publisher = "NLM (Medline)",

number = "4",

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Maimaitiyiming, Y, Wang, QQ, Yang, C, Ogra, Y, Lou, Y, Smith, CA, Hussain, L, Shao, YM, Lin, J, Liu, J, Wang, L, Zhu, Y, Lou, H, Huang, Y, Li, X, Chang, KJ, Chen, H, Li, H, Huang, Y, Tse, E, Sun, J, Bu, N, Chiou, SH, Zhang, YF, Hua, HY, Ma, LY, Huang, P, Ge, MH, Cao, FL, Cheng, X, Sun, H, Zhou, J, Vasliou, V, Xu, P, Jin, J, Bjorklund, M, Zhu, HH, Hsu, CH & Naranmandura, H 2021, 'Hyperthermia Selectively Destabilizes Oncogenic Fusion Proteins', Blood cancer discovery, vol. 2, no. 4, pp. 388-401. https://doi.org/10.1158/2643-3230.BCD-20-0188

TY - JOUR

T1 - Hyperthermia Selectively Destabilizes Oncogenic Fusion Proteins

AU - Maimaitiyiming, Yasen

AU - Wang, Qian Qian

AU - Yang, Chang

AU - Ogra, Yasumitsu

AU - Lou, Yinjun

AU - Smith, Clayton A.

AU - Hussain, Liaqat

AU - Shao, Yi Ming

AU - Lin, Jiebo

AU - Liu, Jinfeng

AU - Wang, Lingfang

AU - Zhu, Yong

AU - Lou, Haiyan

AU - Huang, Yuan

AU - Li, Xiaoxia

AU - Chang, Kao Jung

AU - Chen, Hao

AU - Li, Hongyan

AU - Huang, Ying

AU - Tse, Eric

AU - Sun, Jie

AU - Bu, Na

AU - Chiou, Shih Hwa

AU - Zhang, Yan Fang

AU - Hua, Hao Ying

AU - Ma, Li Ya

AU - Huang, Ping

AU - Ge, Ming Hua

AU - Cao, Feng Lin

AU - Cheng, Xiaodong

AU - Sun, Hongzhe

AU - Zhou, Jin

AU - Vasliou, Vasilis

AU - Xu, Pengfei

AU - Jin, Jie

AU - Bjorklund, Mikael

AU - Zhu, Hong Hu

AU - Hsu, Chih Hung

AU - Naranmandura, Hua

PY - 2021/7/1

Y1 - 2021/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85119270701&partnerID=8YFLogxK

U2 - 10.1158/2643-3230.BCD-20-0188

DO - 10.1158/2643-3230.BCD-20-0188

M3 - Article

C2 - 34238760

AN - SCOPUS:85119270701

SN - 2643-3230

VL - 2

SP - 388

EP - 401

JO - Blood cancer discovery

JF - Blood cancer discovery

IS - 4

ER -

Hyperthermia Selectively Destabilizes Oncogenic Fusion Proteins

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