Department of Health Sciences and Technology, Samsung Advanced Institute for Health Science and Technology (SAIHST), Sungkyunkwan University, Seoul 06351, Korea.
Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
Int J Mol Sci. 2019 Apr 6;20(7):1717. doi: 10.3390/ijms20071717.
The fusion is a frequent chromosomal alteration in acute myeloid leukemias (AMLs). Although fusion protein has pivotal roles in the development of AMLs with the fusion, , fusion protein is difficult to target, as it lacks kinase activities. Here, we used bioinformatic tools to elucidate targetable signaling pathways in AMLs with fusion. After analysis of 93 AML cases from The Cancer Genome Atlas (TCGA) database, we found expression of 293 genes that correlated to the expression of the fusion gene. Based on these 293 genes, the cyclooxygenase (COX), vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR) pathways were predicted to be specifically activated in AMLs with fusion. Moreover, the in vitro proliferation of AML cells with fusion decreased significantly more than that of AML cells without the fusion, when the pathways were inhibited pharmacologically. The results indicate that novel targetable signaling pathways could be identified by the analysis of the gene expression features of AMLs with non-targetable genetic alterations. The elucidation of specific molecular targets for AMLs that have a specific genetic alteration would promote personalized treatment of AMLs and improve clinical outcomes.
融合是急性髓系白血病（AML）中常见的染色体改变。尽管融合蛋白在伴有融合的 AML 发病机制中起关键作用，但由于其缺乏激酶活性，融合蛋白难以成为治疗靶点。在这里，我们使用生物信息学工具来阐明伴有融合的 AML 中可靶向的信号通路。在分析了来自癌症基因组图谱（TCGA）数据库的 93 例 AML 病例后，我们发现了 293 个与融合基因表达相关的基因表达。基于这 293 个基因，预测伴有融合的 AML 中 COX、血管内皮生长因子受体（VEGFR）、血小板衍生生长因子受体（PDGFR）和成纤维细胞生长因子受体（FGFR）通路被特异性激活。此外，当这些通路被药理学抑制时，伴有融合的 AML 细胞的体外增殖明显低于无融合的 AML 细胞。这些结果表明，通过分析不可靶向遗传改变的 AML 的基因表达特征，可以鉴定新的可靶向信号通路。阐明具有特定遗传改变的 AML 的特定分子靶标将促进 AML 的个体化治疗并改善临床结局。
