基于基因测序、病证结合的骨髓增生异常综合征患者对复方青黄散治疗反应的预测指标研究

Myelodysplastic syndromes (MDS) are a group of clonal disorders of haematopoietic stem cells. There are some reliable markers for predicting response to erythropoietin, immunosuppressants, and demethylating drugs in the treatment of MDS. Our previous studies have shown that the efficacy of the compound QingHuang Powder (QHP) was associated with the clone types, which indicated that the type of clone can be used, to a certain extent, as a marker to predict response to compound QHP, but it is still not accurate. The recurrent gene mutations have been detected by gene sequencing in MDS. Detection of gene mutation has entered the guidelines of MDS treatment. Whether there are MDS patients with some gene mutations selectively responsed to compound QHP since the gene mutations having been detected in MDS ? Whether there are relationships between the gene mutations and the TCM syndromes since the treatment of MDS is based on TCM syndromes?.This study is to investigate the abnormal genes targeted on TCM syndromes by gene sequencing in MDS patients, which will provides a molecular basis for the treatment of MDS based on TCM syndromes. To find out the markers for predicting response to compound QHP in the treatment of MDS by analyzing the association of the efficacy of compound QHP with TCM syndromes and targeted genes, which will provide the precision medicine to MDS patients by selecting the appropriate patients selectively responsed to compound QHP.

骨髓增生异常综合征（MDS）是一组起源于造血干/祖细胞的获得性克隆性疾患。治疗MDS的促红细胞生成素、免疫抑制剂、去甲基化药物已有可靠的疗效预测指标。我们的前期研究表明，复方青黄散治疗MDS的疗效具有克隆选择性，克隆类型在一定程度上可以作为其治疗反应的预测标记，但仍不够精准。基因测序方法检测到MDS重现性基因突变，基因突变的检测已经进入MDS的诊疗指南。MDS存在基因突变，复方青黄散治疗MDS是否也有一定的基因选择性呢？辨证分型是中医治疗本病的根据，MDS基因改变与中医辨证分型之间是否存在关系呢？.本研究通过对MDS患者进行基因测序，分析不同证型的异常靶基因，为中医辨证分型治疗MDS提供分子依据。通过研究复方青黄散治疗MDS的疗效与辨证分型、异常基因靶点之间的关系，寻找MDS患者对复方青黄散治疗反应的预测指标，选择合适患者用复方青黄散治疗，达到复方青黄散对MDS患者的精准治疗。

本项目“基于基因测序、病证结合的骨髓增生异常综合征（MDS）患者对复方青黄散治疗反应的预测指标研究”，通过发现MDS患者的受累基因以及异常基因类型，深入探讨MDS的分子学发病机理；了解MDS密切相关的基因靶点与中医证型之间的关系，为中医辨证分型治疗MDS提供分子基础理论依据；基于异常基因与中医证型，寻找复方青黄散发挥治疗作用的基因靶点，精准有效地指导临床用药，为中医药治疗MDS的个体化治疗方案提供示范作用。.本研究发现：（1）超过60%的MDS患者存在基因突变；以多基因（≥2个）突变为主。最常见的基因突变为SF3B1、U2AF1 、ASXL1、TET2以及TP53。突变基因功能组多见于RNA剪切组、DNA甲基化组以及染色质重塑。（2）MDS基因突变的高发生率、突变的多样性以及在不同人群中分布的差异性，表明基因突变在MDS发病机制的相关性、MDS患者的异质性以及MDS患者个体化治疗的重要性。.本研究还发现：（1）MDS患者辨证分型以脾肾阳虚、毒瘀阻滞证为多见证型。（2）MDS患者脾肾阳虚、毒瘀阻滞证与气阴两虚、毒瘀阻滞证之间，在骨髓原始细胞比例、国际预后积分系统（IPSS-R）危度、伴随多个（≥2个）基因突变比例、基因突变类型以及突变基因功能组等方面均存在显著差异，为MDS中医辨证分型提供客观精准指标。（3）MDS 密切相关的基因靶点与中医证型之间的关系，为MDS病证结合精准化个体治疗提供依据。.本研究结果表明：（1）中医证型、染色体预后核型、危度分层（IPSS-R）、有无基因突变以及基因突变个数与突变基因功能组可作为MDS患者对复方青黄散治疗反应的预测指标。（2 ）复方青黄散发挥治疗作用的基因靶点，可以精准有效地指导临床用药，为中医药治疗MDS的个体化治疗方案提供示范作用。