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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wolters Kluwer Health
2023-10-01
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| Series: | Blood Science |
| Online Access: | http://journals.lww.com/10.1097/BS9.0000000000000168 |
| _version_ | 1797449536911704064 |
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| author | Huijun Huang Jinqin Liu Lin Yang Yiru Yan Meng Chen Bing Li Zefeng Xu Tiejun Qin Shiqiang Qu Liang Wang Gang Huang Yue Chen Zhijian Xiao |
| author_facet | Huijun Huang Jinqin Liu Lin Yang Yiru Yan Meng Chen Bing Li Zefeng Xu Tiejun Qin Shiqiang Qu Liang Wang Gang Huang Yue Chen Zhijian Xiao |
| author_sort | Huijun Huang |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-09T14:26:24Z |
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| id | doaj.art-0510e0ed356f4e07a7c5db15ead7f451 |
| institution | Directory Open Access Journal |
| issn | 2543-6368 |
| language | English |
| last_indexed | 2024-03-09T14:26:24Z |
| publishDate | 2023-10-01 |
| publisher | Wolters Kluwer Health |
| record_format | Article |
| series | Blood Science |
| spelling | doaj.art-0510e0ed356f4e07a7c5db15ead7f4512023-11-28T07:05:42ZengWolters Kluwer HealthBlood Science2543-63682023-10-015425826810.1097/BS9.0000000000000168202312000-00004Micheliolide exerts effects in myeloproliferative neoplasms through inhibiting STAT3/5 phosphorylation via covalent binding to STAT3/5 proteinsHuijun Huang0Jinqin Liu1Lin Yang2Yiru Yan3Meng Chen4Bing Li5Zefeng Xu6Tiejun Qin7Shiqiang Qu8Liang Wang9Gang Huang10Yue Chen11Zhijian Xiao12a State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, Chinaa State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, Chinaa State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, Chinaa State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, Chinaa State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, Chinaa State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, Chinaa State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, Chinab MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, Chinaa State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, Chinac State Key Laboratory of Medicinal Chemical Biology, College of Chemistry, Nankai University, 94 Weijin Road, Tianjin, Chinad Department of Cell System & Anatomy, the University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USAc State Key Laboratory of Medicinal Chemical Biology, College of Chemistry, Nankai University, 94 Weijin Road, Tianjin, Chinaa State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, ChinaRuxolitinib 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.http://journals.lww.com/10.1097/BS9.0000000000000168 |
| spellingShingle | Huijun Huang Jinqin Liu Lin Yang Yiru Yan Meng Chen Bing Li Zefeng Xu Tiejun Qin Shiqiang Qu Liang Wang Gang Huang Yue Chen Zhijian Xiao Micheliolide exerts effects in myeloproliferative neoplasms through inhibiting STAT3/5 phosphorylation via covalent binding to STAT3/5 proteins Blood Science |
| 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 |
| url | http://journals.lww.com/10.1097/BS9.0000000000000168 |
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