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Abstract：
Purpose: Chronic myeloid leukemia stem cells (CML-LSCs) are posited as the primary instigators of resistance to tyrosine kinase inhibitors (TKIs) and recurrence of CML. Ubiquitination, a post-translational modification, has been implicated in the worsening process of CML. A more detailed understanding of their crosstalk needs further investigation. Our research aims to explore the potential ubiquitination-related genes in CML-LSC using bioinformatics analysis that might be the target for the eradication of LSCs. Methods: The ubiquitination modification-related differentially expressed genes (UUC-DEGs) between normal hematopoietic stem cells (HSCs) and LSCs were obtained from GSE47927 and iUUCD database. Subsequently, the hub UUC-DEGs were identified through protein-protein interaction (PPI) network analysis utilizing the STRING database and the MCODE plug-in within the Cytoscape platform. The upstream regulation network of the hub UUC-DEGs was studied by hTFtarget, PROMO, miRDB and miRWalk databases respectively. Then the correlation between the hub UUC-DEGs and the immune cells was analyzed by the CIBERSORT algorithm and \"ggcorrplot\" package. Finally, we validated the function of hub UUC-DEGs in CML animal models, CML cell lines and CD34+ cells of the GSE24739 dataset. Results: There is a strong association between the 4 hub UUC genes (AURKA, Fancd2, Cdc20 and Uhrf1) of LSCs and the infiltration of CD4+/CD8+ T cells, NK cells and monocytes. 8 TFs and 23 miRNAs potentially targeted these 4 hub genes were constructed. Among these hub genes, Fancd2, Cdc20 and Uhrf1 were found to be highly expressed in CML-LSC, which knocking down resulted in significant inhibition of CML cell proliferation. Conclusions: From the perspective of bioinformatics analysis, UHRF1 and CDC20 were identified as the novel key ubiquitination-related genes in CML-LSCs and the pathogenesis of CML.
摘要：
目的：慢性粒细胞白血病干细胞（CML-LSCs）被认为是酪氨酸激酶抑制剂（TKIs）耐药和CML复发的主要诱因。泛素化,翻译后修饰，与慢性粒细胞白血病的恶化过程有关。更详细地了解他们的串扰需要进一步调查。我们的研究旨在利用生物信息学分析探索CML-LSC中潜在的泛素化相关基因，这些基因可能是根除LSCs的靶标。方法：从GSE47927和iUCD数据库获得正常造血干细胞（HSC）和LSC之间的泛素化修饰相关差异表达基因（UUC-DEGs）。随后，利用STRING数据库和Cytoscape平台内的MCODE插件,通过蛋白质-蛋白质相互作用(PPI)网络分析鉴定了中心UUC-DEGs.hTFtarget研究了集线器UUC-DEGs的上游调节网络，PROMO,miRDB和miRWalk数据库。然后通过CIBERSORT算法和“ggcorrplot”软件包分析集线器UUC-DEGS与免疫细胞之间的相关性。最后,我们验证了集线器UUC-DEGs在CML动物模型中的功能，GSE24739数据集的CML细胞系和CD34+细胞。结果：4个hubUUC基因之间存在很强的关联(AURKA，Fancd2，Cdc20和Uhrf1）的LSCs和CD4+/CD8+T细胞的浸润，NK细胞和单核细胞。构建了8个TFs和23个潜在靶向这4个hub基因的miRNA。在这些中枢基因中，发现Fancd2，Cdc20和Uhrf1在CML-LSC中高度表达，敲低导致CML细胞增殖的显著抑制。结论:从生物信息学分析的角度,UHRF1和CDC20被鉴定为CML-LSCs和CML发病机制中的新的关键泛素化相关基因。
