文章：

母胚亮氨酸拉链激酶是弥漫性大B细胞淋巴瘤和套细胞淋巴瘤的新靶点

Maternal embryonic leucine zipper kinase is a novel target for diffuse large B cell lymphoma and mantle cell lymphoma

原文发布日期：2019-11-18

DOI: 10.1038/s41408-019-0249-x

类型: Article

开放获取: 是

英文摘要：

Diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are among the most aggressive B cell non-Hodgkin lymphomas. Maternal embryonic leucine zipper kinase (MELK) plays a role in cancer cell cycle progression and is associated with poor prognosis in several cancer cell types. In this study, the role of MELK in DLBCL and MCL and the therapeutic potential of MELK targeting is evaluated. MELK is highly expressed in DLBCL and MCL patient samples, correlating with a worse clinical outcome in DLBCL. Targeting MELK, using the small molecule OTSSP167, impaired cell growth and survival and induced caspase-mediated apoptosis in the lymphoma cells. Western blot analysis revealed that MELK targeting decreased the phosphorylation of FOXM1 and the protein levels of EZH2 and several mitotic regulators, such as Cdc25B, cyclin B1, Plk-1, and Aurora kinases. In addition, OTSSP167 also sensitized the lymphoma cells to the clinically relevant Bcl-2 inhibitor venetoclax by strongly reducing Mcl1 levels. Finally, OTSSP167 treatment of A20-inoculated mice resulted in a significant prolonged survival. In conclusion, targeting MELK with OTSSP167 induced strong anti-lymphoma activity both in vitro and in vivo. These findings suggest that MELK could be a potential new target in these aggressive B cell malignancies.
 

摘要翻译： 

弥漫性大B细胞淋巴瘤（DLBCL）与套细胞淋巴瘤（MCL）属于最具侵袭性的B细胞非霍奇金淋巴瘤。母源性胚胎亮氨酸拉链激酶（MELK）在癌细胞周期进程中发挥作用，并与多种癌细胞类型的不良预后相关。本研究评估了MELK在DLBCL和MCL中的作用及其靶向治疗潜力。MELK在DLBCL和MCL患者样本中高表达，且与DLBCL较差的临床结局相关。使用小分子OTSSP167靶向MELK可抑制淋巴瘤细胞的生长存活，并诱导半胱天冬酶介导的凋亡。蛋白质印迹分析显示，MELK靶向作用降低了FOXM1的磷酸化水平，并降低了EZH2及多种有丝分裂调控因子（如Cdc25B、细胞周期蛋白B1、Plk-1和极光激酶）的蛋白水平。此外，OTSSP167通过显著降低Mcl1水平，增强淋巴瘤细胞对临床相关Bcl-2抑制剂维奈托克的敏感性。最后，对接种A20细胞的小鼠使用OTSSP167治疗可显著延长其生存期。综上所述，OTSSP167靶向MELK在体外和体内均表现出强烈的抗淋巴瘤活性。这些发现表明，MELK可能成为这类侵袭性B细胞恶性肿瘤的潜在新靶点。

原文链接：

Maternal embryonic leucine zipper kinase is a novel target for diffuse large B cell lymphoma and mantle cell lymphoma