Background/Objectives:NRASmutations are found in approximately 10% of patients with acute myeloid leukemia (AML), with nearly half of those occurring at codon 12, but little is known about how differing G12 mutants affect cancer cell activity.Methods: A novel bioinformatic technique, differential expression and pathway ranking (DEAPR), was used to identify the most prominent changes in terms of both individual genes and associated pathways when comparing AML THP-1 cells containing anNRASG12Dmutation with B11 cells, which are THP-1-derived cells with theNRASG12Dallele removed and a dox-inducibleNRASG12Vallele introduced.Results: In total, 1456 differentially expressed (DE) protein-coding genes were uniquely associated to theNRASG12Dmutation, while 585 DE protein-coding genes were specific to theNRASG12Vmutation. The innate immune system pathway was prominent in both mutant-specific lists, even though the genes involved were not in both lists. Furthermore, the two calprotectin genes (S100A8andS100A9), also associated with innate immunity, were upregulated in theNRASG12Dmutant and downregulated in theNRASG12Vmutant.Conclusions: This study, using the DEAPR strategy, clearly demonstrates the dramatic changes associated with two seemingly similarNRASmutations, suggesting the deployment of different treatment strategies based on the type ofNRASmutation present.
背景/目的：NRAS突变在约10%的急性髓系白血病（AML）患者中被发现，其中近半数发生在第12密码子，但关于不同G12突变如何影响癌细胞活性的研究甚少。方法：本研究采用新型生物信息学技术——差异表达与通路排序分析（DEAPR），通过比较携带NRAS G12D突变的AML THP-1细胞与B11细胞（该细胞系源自THP-1，已敲除NRAS G12D等位基因并引入多西环素诱导型NRAS G12V等位基因），系统识别了在单个基因及相关通路层面最显著的变化。结果：共发现1456个差异表达（DE）蛋白编码基因与NRAS G12D突变特异性相关，而585个DE蛋白编码基因特异于NRAS G12V突变。固有免疫系统通路在两种突变特异性基因列表中均显著富集，尽管所涉及的基因并不重合。值得注意的是，与固有免疫相关的两种钙卫蛋白基因（S100A8和S100A9）在NRAS G12D突变中表达上调，而在NRAS G12V突变中表达下调。结论：本研究通过DEAPR策略清晰揭示了两种看似相似的NRAS突变所引发的显著生物学差异，提示临床应根据NRAS突变类型制定差异化的治疗策略。
肿瘤(癌症)患者之家