慢性髓系白血病（CML）是一种起源于造血干细胞的侵袭性恶性肿瘤。伊马替尼（IM），作为第一代酪氨酸激酶抑制剂，极大地提高了CML患者的生活质量。然而，由于酪氨酸激酶抑制剂（TKIs）耐药导致的复发和治疗失败，一些CML患者的预后仍然不佳。因此，我们旨在寻找伊马替尼耐药的潜在信号通路和特定生物标志物。我们在伊马替尼敏感的K562细胞（IS-K562）和伊马替尼耐药的K562细胞（IR-K562）中进行了mRNA和miRNA表达谱分析。鉴定差异表达基因（DEGs），并进行通路富集分析以探索潜在机制。构建蛋白质相互作用（PPI）网络和miRNA-mRNA调控网络以探索这些基因之间的潜在关系。进一步实验使用RT-qPCR，Western blot和CCK8进行验证。共鉴定到623个DEGs和61个差异表达的miRNA。GO分析显示DEGs主要参与细胞粘附、细胞迁移、分化和炎症反应。KEGG分析显示DEGs主要富集于Rap1信号通路、焦点粘附、蛋白多糖和癌症转录调控、调节干细胞多能性等信号通路以及部分免疫相关通路。PPI网络和miRNA-mRNA调控网络揭示了基因之间多样的相互关系。最后，我们证实了RHoGDI2在伊马替尼耐药中发挥了关键作用。基因与信号通路之间的动态相互作用与TKIs耐药有关，RHoGDI2被确定为IR-K562的生物标志物。

Chronic myeloid leukemia (CML) is an aggressive malignancy originating from hematopoietic stem cells. Imatinib (IM), the first-generation tyrosine kinase inhibitor, has greatly improved theliving quality of CML patients. However, owing to the recurrence and treatment failure coming from tyrosine kinase inhibitor (TKIs) resistance, some CML patients still bear poor prognosis. Therefore, we aimed to seek potential signaling pathways and specific biomarkers for imatinib resistance.We performed mRNA and miRNA expression profiling in imatinib-sensitive K562 cells (IS-K562) and imatinib-resistant K562 cells (IR-K562). Differentially expressed genes (DEGs) were identified and pathway enrichment analyses were performed to explore the potential mechanism. The protein-protein interaction (PPI) network and miRNA-mRNA regulatory network were constructed to explore potential relationships among these genes. RT-qPCR, western blot and CCK8 were used for further experiments.A total of 623 DEGs and 61 differentially expressed miRNAs were identified. GO revealed that DEGs were mainly involved in cell adhesion, cell migration, differentiation, and inflammatory response. KEGG revealed that DEGs were typically enriched in the Rap1 signaling pathway, focal adhesion, proteoglycans and transcriptional misregulation in cancer, signaling pathways regulating pluripotency of stem cells and some immune-related pathways. The protein-protein interaction (PPI) network and miRNA-mRNA regulatory network revealed a web of diverse connections among genes. Finally, we proved that RHoGDI2 played a critical role in imatinib resistance.The dynamic interplay between genes and signaling pathways is associated with TKIs resistance and RHoGDI2 is identified as a biomarker in IR-K562.