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Micheliolide exerts effects in myeloproliferative neoplasms through inhibiting STAT3/5 phosphorylation via covalent binding to STAT3/5 proteins

Ruxolitinib is a cornerstone of management for some subsets of myeloproliferative neoplasms (MPNs); however, a considerable number of patients respond suboptimally. Here, we evaluated the efficacy of micheliolide (MCL), a natural guaianolide sesquiterpene lactone, alone or in combination with ruxoli...

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Autores principales: Huang, Huijun, Liu, Jinqin, Yang, Lin, Yan, Yiru, Chen, Meng, Li, Bing, Xu, Zefeng, Qin, Tiejun, Qu, Shiqiang, Wang, Liang, Huang, Gang, Chen, Yue, Xiao, Zhijian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10629731/
https://www.ncbi.nlm.nih.gov/pubmed/37941916
http://dx.doi.org/10.1097/BS9.0000000000000168
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author Huang, Huijun
Liu, Jinqin
Yang, Lin
Yan, Yiru
Chen, Meng
Li, Bing
Xu, Zefeng
Qin, Tiejun
Qu, Shiqiang
Wang, Liang
Huang, Gang
Chen, Yue
Xiao, Zhijian
author_facet Huang, Huijun
Liu, Jinqin
Yang, Lin
Yan, Yiru
Chen, Meng
Li, Bing
Xu, Zefeng
Qin, Tiejun
Qu, Shiqiang
Wang, Liang
Huang, Gang
Chen, Yue
Xiao, Zhijian
author_sort Huang, Huijun
collection PubMed
description Ruxolitinib is a cornerstone of management for some subsets of myeloproliferative neoplasms (MPNs); however, a considerable number of patients respond suboptimally. Here, we evaluated the efficacy of micheliolide (MCL), a natural guaianolide sesquiterpene lactone, alone or in combination with ruxolitinib in samples from patients with MPNs, JAK2V617F-mutated MPN cell lines, and a Jak2V617F knock-in mouse model. MCL effectively suppressed colony formation of hematopoietic progenitors in samples from patients with MPNs and inhibited cell growth and survival of MPN cell lines in vitro. Co-treatment with MCL and ruxolitinib resulted in greater inhibitory effects compared with treatment with ruxolitinib alone. Moreover, dimethylaminomicheliolide (DMAMCL), an orally available derivative of MCL, significantly increased the efficacy of ruxolitinib in reducing splenomegaly and cytokine production in Jak2V617F knock-in mice without evident effects on normal hematopoiesis. Importantly, MCL could target the Jak2V617F clone and reduce mutant allele burden in vivo. Mechanistically, MCL can form a stable covalent bond with cysteine residues of STAT3/5 to suppress their phosphorylation, thus inhibiting JAK/STAT signaling. Overall, these findings suggest that MCL is a promising drug in combination with ruxolitinib in the setting of suboptimal response to ruxolitinib.
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spelling pubmed-106297312023-11-08 Micheliolide exerts effects in myeloproliferative neoplasms through inhibiting STAT3/5 phosphorylation via covalent binding to STAT3/5 proteins Huang, Huijun Liu, Jinqin Yang, Lin Yan, Yiru Chen, Meng Li, Bing Xu, Zefeng Qin, Tiejun Qu, Shiqiang Wang, Liang Huang, Gang Chen, Yue Xiao, Zhijian Blood Sci Research Articles Ruxolitinib is a cornerstone of management for some subsets of myeloproliferative neoplasms (MPNs); however, a considerable number of patients respond suboptimally. Here, we evaluated the efficacy of micheliolide (MCL), a natural guaianolide sesquiterpene lactone, alone or in combination with ruxolitinib in samples from patients with MPNs, JAK2V617F-mutated MPN cell lines, and a Jak2V617F knock-in mouse model. MCL effectively suppressed colony formation of hematopoietic progenitors in samples from patients with MPNs and inhibited cell growth and survival of MPN cell lines in vitro. Co-treatment with MCL and ruxolitinib resulted in greater inhibitory effects compared with treatment with ruxolitinib alone. Moreover, dimethylaminomicheliolide (DMAMCL), an orally available derivative of MCL, significantly increased the efficacy of ruxolitinib in reducing splenomegaly and cytokine production in Jak2V617F knock-in mice without evident effects on normal hematopoiesis. Importantly, MCL could target the Jak2V617F clone and reduce mutant allele burden in vivo. Mechanistically, MCL can form a stable covalent bond with cysteine residues of STAT3/5 to suppress their phosphorylation, thus inhibiting JAK/STAT signaling. Overall, these findings suggest that MCL is a promising drug in combination with ruxolitinib in the setting of suboptimal response to ruxolitinib. Lippincott Williams & Wilkins 2023-07-12 /pmc/articles/PMC10629731/ /pubmed/37941916 http://dx.doi.org/10.1097/BS9.0000000000000168 Text en Copyright © 2023 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the Chinese Medical Association (CMA) and Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College (IHCAMS). https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY) (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Huang, Huijun
Liu, Jinqin
Yang, Lin
Yan, Yiru
Chen, Meng
Li, Bing
Xu, Zefeng
Qin, Tiejun
Qu, Shiqiang
Wang, Liang
Huang, Gang
Chen, Yue
Xiao, Zhijian
Micheliolide exerts effects in myeloproliferative neoplasms through inhibiting STAT3/5 phosphorylation via covalent binding to STAT3/5 proteins
title Micheliolide exerts effects in myeloproliferative neoplasms through inhibiting STAT3/5 phosphorylation via covalent binding to STAT3/5 proteins
title_full Micheliolide exerts effects in myeloproliferative neoplasms through inhibiting STAT3/5 phosphorylation via covalent binding to STAT3/5 proteins
title_fullStr Micheliolide exerts effects in myeloproliferative neoplasms through inhibiting STAT3/5 phosphorylation via covalent binding to STAT3/5 proteins
title_full_unstemmed Micheliolide exerts effects in myeloproliferative neoplasms through inhibiting STAT3/5 phosphorylation via covalent binding to STAT3/5 proteins
title_short Micheliolide exerts effects in myeloproliferative neoplasms through inhibiting STAT3/5 phosphorylation via covalent binding to STAT3/5 proteins
title_sort micheliolide exerts effects in myeloproliferative neoplasms through inhibiting stat3/5 phosphorylation via covalent binding to stat3/5 proteins
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10629731/
https://www.ncbi.nlm.nih.gov/pubmed/37941916
http://dx.doi.org/10.1097/BS9.0000000000000168
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