Micheliolide 通过与 STAT3/5 蛋白共价结合抑制 STAT3/5 磷酸化，从而在骨髓增生性肿瘤中发挥作用。
Micheliolide exerts effects in myeloproliferative neoplasms through inhibiting STAT3/5 phosphorylation via covalent binding to STAT3/5 proteins.
发表日期：2023 Oct
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
来源：
Experimental Hematology & Oncology
摘要：
鲁索替尼是治疗某些骨髓增生性肿瘤 (MPN) 亚型的基石；然而，相当多的患者反应不佳。在这里，我们评估了米凯洛内酯（MCL）（一种天然愈创木酚内酯倍半萜内酯）单独或与鲁索替尼联合使用在来自 MPN 患者、JAK2V617F 突变 MPN 细胞系和 Jak2V617F 敲入小鼠模型的样本中的功效。 MCL 有效抑制 MPN 患者样本中造血祖细胞的集落形成，并在体外抑制 MPN 细胞系的细胞生长和存活。与单独使用鲁索替尼治疗相比，MCL 和鲁索替尼联合治疗产生了更大的抑制作用。此外，二甲氨基米其利内酯 (DMAMCL) 是一种口服的 MCL 衍生物，可显着提高鲁索替尼在减少 Jak2V617F 敲入小鼠脾肿大和细胞因子产生方面的功效，且对正常造血没有明显影响。重要的是，MCL 可以靶向 Jak2V617F 克隆并减少体内突变等位基因负担。从机制上讲，MCL可以与STAT3/5的半胱氨酸残基形成稳定的共价键，抑制其磷酸化，从而抑制JAK/STAT信号传导。总体而言，这些研究结果表明，在鲁索替尼反应欠佳的情况下，MCL 与鲁索替尼联合使用是一种很有前途的药物。版权所有 © 2023 作者。由威科健康公司代表中华医学会 (CMA) 和中国医学科学院血液学研究所发布
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.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).