尼洛替尼和伊马替尼对慢性粒细胞 白血病表达谱的影响

Effect of Nilotinib and Imatinib on expression profile of chronic myelocytic leukemia

摘要:

目的 探索尼洛替尼和伊马替尼对慢性粒细胞白血病（CML）细胞基因表达谱的影响，阐明酪氨酸 激酶抑制剂（TKI）抑制白血病的分子机制。方法 从在线基因表达数据库中下载表达谱数据集GSE19567， 利用BRB-ArrayTools 软件进行质量控制并筛选差异表达基因（DEGs ），然后分别对差异基因进行GO 功能 富集分析、KEGG 通路富集分析、pathway 互作网络和基因互作网络分析。结果 共筛选出差异基因519 个， 其中177 个上调表达，342 个下调表达。GO 富集分析发现DEGs 主要涉及小分子代谢、血液凝固、转录调控、 细胞增殖与凋亡调控等生物过程，发挥的分子功能集中在蛋白结合、蛋白二聚化、序列特异性DNA 结合和 ATP 结合等。KEGG 富集分析发现代谢通路、PI3K-Akt 信号通路、Jak-STAT 信号通路和HIF-1 信号通路 等pathway 显著富集。网络分析挖掘出的核心基因有SHMT 2、CBS 、CTH 、HK 2，核心pathway 包括MAPK 信号通路、细胞周期和细胞凋亡等。结论 酪氨酸激酶抑制剂影响了CML 细胞代谢通路和信号转导通路的相 关基因，通过细胞周期阻滞和诱导凋亡等机制抑制白血病，为白血病的靶向治疗提供了基础。

Abstract:

Objective To investigate the effect of Nilotinib and Imatinib on gene expression profile of chronic myelocytic leukemia (CML) cells and clarify the molecular mechanism underlying the suppression of tyrosine kinase inhibitors against leukemia. Methods The expression profiling dataset GSE19567 was downloaded from the online Gene Expression Omnibus database. The BRB-ArrayTools software was applied to control quality and identify the differentially-expressed genes (DEGs), then the GO function enrichment, KEGG pathway enrichment, pathway relation network, and gene interaction network analyses were preformed based on these differential genes. Results In total, 519 differential genes were screened out, of which 177 genes were up-regulated and 342 genes were down-regulated. GO enrichment analysis revealed that DEGs were mainly involved in biological processes of small molecule metabolism, blood coagulation, transcriptional regulation, regulation of cell proliferation and apoptosis, and performed the molecular functions of protein binding, protein dimerization activity, sequence-specific DNA binding and ATP binding. KEGG analysis showed that DEGs were mostly enriched in metabolic pathway, PI3K-Akt signaling pathway, JAK-STAT signaling pathway, and HIF-1 signaling pathway. The network analyses identified the hub genes such as SHMT2, CBS, CTH and HK2, and core pathways including MAPK signaling pathway, cell cycle and apoptosis. Conclusions Tyrosine kinase inhibitors affect the genes involved in metabolic and signal transduction pathways, and the mechanism of suppression of CML cells may include cell cycle arrest and induction of apoptosis, which provides the foundation for further developing targeted treatments for leukemia.