文章：

体外和离体基因表达谱分析揭示，HSPs和UPR基因的差异动力学反应与多发性骨髓瘤的蛋白酶体抑制剂耐药性相关

In vitro and ex vivo gene expression profiling reveals differential kinetic response of HSPs and UPR genes is associated with PI resistance in multiple myeloma

原文发布日期：2020-07-28

DOI: 10.1038/s41408-020-00344-9

类型: Article

开放获取: 是

英文摘要：

Extensive inter-individual variation in response to chemotherapy (sensitive vs resistant tumors) is a serious cause of concern in the treatment of multiple myeloma (MM). In this study, we used human myeloma cell lines (HMCLs), and patient-derived CD138+ cells to compare kinetic changes in gene expression patterns between innate proteasome inhibitor (PI)-sensitive and PI-resistant HMCLs following test dosing with the second-generation PI Ixazomib. We found 1553 genes that changed significantly post treatment in PI-sensitive HMCLs compared with only seven in PI-resistant HMCLs (p < 0.05). Genes that were uniquely regulated in PI-resistant lines were RICTOR (activated), HNF4A, miR-16-5p (activated), MYCN (inhibited), and MYC (inhibited). Ingenuity pathway analysis (IPA) using top kinetic response genes identified the proteasome ubiquitination pathway (PUP), and nuclear factor erythroid 2-related factor 2 (NRF2)-mediated oxidative stress response as top canonical pathways in Ix-sensitive cell lines and patient-derived cells, whereas EIF2 signaling and mTOR signaling pathways were unique to PI resistance. Further, 10 genes were common between our in vitro and ex vivo post-treatment kinetic PI response profiles and Shaughnessy’s GEP80-postBz gene expression signature, including the high-risk PUP gene PSMD4. Notably, we found that heat shock proteins and PUP pathway genes showed significant higher upregulation in Ix-sensitive lines compared with the fold-change in Ix-resistant myelomas.
 

摘要翻译： 

化疗反应（敏感肿瘤与耐药肿瘤）中广泛的个体间变异是多发性骨髓瘤治疗中一个严重的问题。本研究使用人多发性骨髓瘤细胞系以及患者来源的CD138+细胞，比较了第二代蛋白酶体抑制剂伊沙佐米测试剂量后，先天蛋白酶体抑制剂敏感与耐药HMCLs之间基因表达模式的动力学变化。我们发现，在PI敏感的HMCLs中，治疗后1553个基因发生显著变化，而PI耐药的HMCLs中仅有7个基因变化（p < 0.05）。在PI耐药细胞系中独特调控的基因包括RICTOR（激活）、HNF4A、miR-16-5p（激活）、MYCN（抑制）和MYC（抑制）。通过顶级动力学响应基因进行的Ingenuity通路分析确定，蛋白酶体泛素化通路和核因子E2相关因子2介导的氧化应激反应是伊沙佐米敏感细胞系和患者来源细胞中的主要经典通路，而EIF2信号和mTOR信号通路是PI耐药所独有的。此外，我们的体外和离体治疗后动力学PI响应谱与Shaughnessy的GEP80-postBz基因表达特征之间有10个基因重叠，包括高风险PUP基因PSMD4。值得注意的是，我们发现热休克蛋白和PUP通路基因在伊沙佐米敏感细胞系中的上调幅度显著高于伊沙佐米耐药骨髓瘤中的变化倍数。

原文链接：

In vitro and ex vivo gene expression profiling reveals differential kinetic response of HSPs and UPR genes is associated with PI resistance in multiple myeloma