College of Basic medical, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, PR China.
College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, PR China.
Mol Genet Genomic Med. 2019 Sep;7(9):e851. doi: 10.1002/mgg3.851. Epub 2019 Aug 2.
Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm that arises from the acquisition of constitutively active BCR-ABL tyrosine kinase in hematopoietic stem cells. The persistence of bone marrow leukemia stem cells (LSCs) is the main cause of TKI resistance and CML relapse. Therefore, finding a key target or pathway to selectively target LSCs is of great significance for the thorough treatment of CML.
In this study, we aimed to identify key microRNAs, microRNA targets and pathways for the treatment of CML LSCs by integrating analyses of three microarray data profiles. We identified 51 differentially expressed microRNAs through integrated analysis of GSE90773 and performed functional gene predictions for microRNAs. Then, GSE11889 and GSE11675 were integrated to obtain differentially expressed genes (DEGs), and the overlapping DEGs were used as models to identify predictive functional genes. Finally, we identified 116 predictive functional genes. Clustering and significant enrichment analysis of 116 genes was based on function and signaling pathways. Subsequently, a protein interaction network was constructed, and module analysis and topology analysis were performed on the network.
A total of 11 key candidate targets and 33 corresponding microRNAs were identified. The key pathways were mainly concentrated on the PI3K/AKT, Ras, JAK/STAT, FoxO and Notch signaling pathways. We also found that LSCs negatively regulated endogenous and exogenous apoptotic pathways to escape from apoptosis.
We identified key candidate targets and pathways for CML LSCs through bioinformatics methods, which improves our understanding of the molecular mechanisms of CML LSCs. These candidate genes and pathways may be therapeutic targets for CML LSCs.
慢性髓性白血病（CML）是一种起源于造血干细胞中获得组成性激活的 BCR-ABL 酪氨酸激酶的骨髓增生性肿瘤。骨髓白血病干细胞（LSCs）的持续存在是 TKI 耐药和 CML 复发的主要原因。因此，找到一个关键的靶点或途径来选择性地靶向 LSCs，对于彻底治疗 CML 具有重要意义。
在这项研究中，我们旨在通过整合三个微阵列数据谱的分析，确定用于治疗 CML LSCs 的关键 microRNA、microRNA 靶标和途径。我们通过整合 GSE90773 分析鉴定了 51 个差异表达的 microRNA，并对 microRNA 进行了功能基因预测。然后，整合 GSE11889 和 GSE11675 以获得差异表达基因（DEGs），并将重叠的 DEGs 用作识别预测功能基因的模型。最后，我们鉴定了 116 个预测功能基因。基于功能和信号通路对 116 个基因进行聚类和显著富集分析。随后，构建蛋白质相互作用网络，并对网络进行模块分析和拓扑分析。
总共鉴定出 11 个关键候选靶标和 33 个相应的 microRNA。关键途径主要集中在 PI3K/AKT、Ras、JAK/STAT、FoxO 和 Notch 信号通路。我们还发现 LSCs 负调控内源性和外源性凋亡途径以逃避凋亡。
我们通过生物信息学方法鉴定了 CML LSCs 的关键候选靶标和途径，这提高了我们对 CML LSCs 分子机制的理解。这些候选基因和途径可能是 CML LSCs 的治疗靶点。
