2. Academic Validation
  3. Micheliolide exerts effects in myeloproliferative neoplasms through inhibiting STAT3/5 phosphorylation via covalent binding to STAT3/5 proteins

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

  • Blood Sci. 2023 Jul 12;5(4):258-268. doi: 10.1097/BS9.0000000000000168.
Huijun Huang 1,  Jinqin Liu 1,  Lin Yang 1,  Yiru Yan 1,  Meng Chen 1,  Bing Li 1 2,  Zefeng Xu 1 2,  Tiejun Qin 2,  Shiqiang Qu 1 2,  Liang Wang 3,  Gang Huang 4 5,  Yue Chen 3,  Zhijian Xiao 1 2 6
Affiliations

Affiliations

  • 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.
PMID: 37941916 DOI: 10.1097/BS9.0000000000000168
Abstract

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.

Keywords

Micheliolide; Myeloproliferative neoplasms; Ruxolitinib; STAT3/5; Suboptimal response.

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