全基因组关联分析高三尖杉酯碱对急性髓系白血病的敏感基因

Homoharringtonine-based three drug induction regimen has recently been used in the patients with de novo acute myeloid leukemia in China. It has been shown to improve the rate of complete remission (CR) and long-term survival in patients, but the addition of more drugs may cause severe myelosuppression and the increase of early death. Thus it is in urgent need to identify genes which may predict the sensitivity to HHT and thereby maximizing efficacy while minimizing drug-related toxicity. Pharmaocogenomics has provided a new and useful way in finding the biomarkers of drug response in recent years. Based on the well-established technology platform of pharmacogenomics, we aim to find candidate genes for drug susceptibility by genome-wide association study. Functional screenings will be done in leukemia cell lines. The candidate genes will be further validated in clinical samples of acute myeloid leukemia. Our study will incorporate the new advances in human genomics and functional pharmacogenomics to find the candidate genes for homoharringtonine sensitivity. It will provide the important basis for individualized therapy for the treatment of acute myeloid leukemia.

高三尖杉酯碱（HHT）为基础的三联化疗方案是国内治疗初发急性髓系白血病（AML）的新方案，它明显提高了患者的缓解率和长期生存率，但药物的累加可能使骨髓抑制更明显，早期死亡率增加。因此寻找HHT药物敏感基因并据此制定靶向群体将有利于提高HHT治疗AML的疗效，减少副作用。药物基因组学筛选药物敏感基因是最近几年新兴的技术。本课题建立在成熟的技术平台上，应用全基因组关联分析寻找高三尖杉酯碱的药物敏感基因，并在白血病细胞株中进行功能性筛选，进而在临床保存的已用过HHT的急性白血病患者标本中验证其药物敏感基因。本课题是结合人类基因组学的最新进展和功能药物基因组学的方法用于筛选HHT药物敏感基因，并结合临床相关分析，为急性白血病的个体化治疗提供重要基础。

高三尖杉酯碱（HTT）在国内广泛应用于急慢性白血病的治疗已数十年。寻找HHT药物敏感基因并据此制定靶向群体将有利于提高疗效，减少副作用。将HHT应用于人淋巴母细胞样细胞系（LCLs），经全基因组关联分析确定与HHT对LCLs杀伤性相关的SNPs。整合SNPs，mRNA表达谱、AUC三者之间的关联，获得与HHT药物敏感相关的靶点基因，进一步运用白血病细胞株进行功能性验证靶点基因。我们的研究发现96个表达探针与HHT AUC相关（P<10-3）, 其中15个探针p<10-4。281个SNPs 与 HHT AUC相关（p<10-4 ），其中18个 SNPs 的p<10-4。关联分析发现4个SNPs与表达及AUC均相关。由此筛选出可能的靶点基因。功能性验证实验发现在人白血病细胞株U937和K562中应用 siRNA抑制CCDC88A, CTBP2, SOCS4基因，HHT的敏感性明显改变。在临床标本中我们也发现CCDC88A, CTBP2表达阳性的患者对HHT的敏感性增加。以上实验提示通过全基因组分析找到的这两个个基因可能是HHT药物敏感性相关的靶点基因。