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

作　　者：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 

机构地区：[1]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,China [2]MDS and MPN Centre,Institute of Hematology and Blood Diseases Hospital,Chinese Academy of Medical Sciences&Peking Union Medical College,Tianjin,China [3]State Key Laboratory of Medicinal Chemical Biology,College of Chemistry,Nankai University,94 Weijin Road,Tianjin,China [4]Department of Cell System&Anatomy,the University of Texas Health Science Center at San Antonio,San Antonio,TX 78229,USA [5]Mays Cancer Center,Joe R.&Teresa Lozano Long School of Medicine,the University of Texas Health Science Center at San Antonio,San Antonio,TX 78229,USA [6]Hematologic Pathology Center,Institute of Hematology and Blood Diseases Hospital,Chinese Academy of Medical Sciences&Peking Union Medical College,Tianjin,China.

出　　处：《Blood Science》2023年第4期258-268,共11页血液科学（英文）

基　　金：Supported in part by Haihe Laboratory of Cell Ecosystem Innovation Fund(22HHXBSS00033);CAMS Initiative Fund for Medical Sciences(Nos.2022-I2M-1-022);Clinical Research Fund of National Clinical Research Centre for Blood Diseases(Nos.2023NCRCA0117 and 2023NCRCA0103);National Natural Science Funds(Nos.82170139,82104785,82070134 and 81530008).

摘　　要：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.

关 键 词：Micheliolide Myeloproliferative neoplasms RUXOLITINIB STAT3/5 Suboptimal response 

分 类 号：R733.3[医药卫生—肿瘤]