Li Cheng-Wei, Lai Tzu-Ying, Chen Bor-Sen
Laboratory of Control and Systems Biology, Department of Electrical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
Oncotarget. 2018 May 4;9(34):23636-23660. doi: 10.18632/oncotarget.25318.
Mutation accumulation and epigenetic alterations in genes are important for carcinogenesis. Because leukemogenesis-related signal pathways have been investigated and microarray sample data have been produced in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and normal cells, systems analysis in coupling pathways becomes possible. Based on system modeling and identification, we could construct the coupling pathways and their associated gene regulatory networks using microarray sample data. By applying system theory to the estimated system model in coupling pathways, we can then obtain transductivity sensitivity, basal sensitivity and error sensitivity of each protein to identify the potential impact of genetic mutations, epigenetic alterations and the coupling of other pathways from the perspective of energy, respectively. By comparing the results in AML, MDS and normal cells, we investigated the potential critical genetic mutations and epigenetic alterations that activate or repress specific cellular functions to promote MDS or AML leukemogenesis. We suggested that epigenetic modification of β-catenin and signal integration of CSLs, AP-2α, STATs, c-Jun and β-catenin could contribute to cell proliferation at AML and MDS. Epigenetic regulation of ERK and genetic mutation of p53 could lead to the repressed apoptosis, cell cycle arrest and DNA repair in leukemic cells. Genetic mutation of JAK, epigenetic regulation of ERK, and signal integration of C/EBPα could result in the promotion of MDS cell differentiation. According to the results, we proposed three drugs, decitabine, genistein, and monorden for preventing AML leukemogenesis, while three drugs, decitabine, thalidomide, and geldanamycin, for preventing MDS leukemogenesis.
基因中的突变积累和表观遗传改变对肿瘤发生至关重要。由于在急性髓系白血病（AML）、骨髓增生异常综合征（MDS）和正常细胞中已经对白血病发生相关信号通路进行了研究并产生了微阵列样本数据，因此耦合通路的系统分析成为可能。基于系统建模与识别，我们可以利用微阵列样本数据构建耦合通路及其相关的基因调控网络。通过将系统理论应用于耦合通路中估计的系统模型，我们能够分别从能量的角度获得每种蛋白质的传导敏感性、基础敏感性和误差敏感性，以识别基因突变、表观遗传改变以及其他通路耦合的潜在影响。通过比较AML、MDS和正常细胞中的结果，我们研究了激活或抑制特定细胞功能以促进MDS或AML白血病发生的潜在关键基因突变和表观遗传改变。我们认为β-连环蛋白的表观遗传修饰以及CSLs、AP-2α、STATs、c-Jun和β-连环蛋白的信号整合可能有助于AML和MDS中的细胞增殖。ERK的表观遗传调控和p53的基因突变可能导致白血病细胞中凋亡受抑制、细胞周期停滞和DNA修复。JAK的基因突变、ERK的表观遗传调控以及C/EBPα的信号整合可能导致MDS细胞分化的促进。根据结果，我们提出了三种药物，即地西他滨、染料木黄酮和莫能菌素用于预防AML白血病发生，而三种药物，即地西他滨、沙利度胺和格尔德霉素用于预防MDS白血病发生。
