去甲基化- - -砷剂治疗骨髓增生异常综合征（MDS）机理研究

Qing-huang Powder, a kind of arsenical, has proven that is available for treatment patients with myelodysplastic anemia(MDS) .In most of MDS patients CPG inlands have been found having high methylation of cancer suppressor gene. Our research on mechanism of curative effect of the arsenical has seen prelimitarily that the arsenical displayed demethylation by methyl competition, through which the arsenical may give MDS patients better results. Based on these data, This task will go on research to study the entire DNA methylation, together with detection of methyl donor, S-adenosylmethionine (SAM) and its downstream metabolin, S-adenosylhomocysteine(SAH) before and after arsenical treatment, to verify that arsenical have the demethylation effect by its detoxication process in MDS.In the meantime, Researches of DNMT3A, IDH1/IDH2 and TET2MDS,the methylation related genes which have high mutational rates in MDS are also brought into our tasks to explain influence of arsenical on DNA methylation related genes. All these results can give more insights into and clarification of the mechanism of arsenical effect on MDS, which can help establish the governing principle of treating MDS with arsenical, definite the subtype of MDS that arsenical aiming at and may promote the clinical effect and in the end give benefit to MDS patients,which may also finally inauguarate new fields in malignent diseases of blood by the arsenical.

以砷剂- - 中药青黄散为主治疗MDS临床疗效肯定。MDS患者大部分存在CpG岛抑癌基因高度甲基化。我们在砷剂疗效机理研究中发现，砷剂因竞争甲基而表现去甲基化作用，从而使MDS过度甲基化基因去甲基化而发挥治疗作用。在此基础上，本课题进一步研究MDS患者砷剂治疗前后全基因甲基化状况及甲基供体S-腺苷甲硫氨酸（SAM）及其供甲基后产物S-腺苷半胱氨酸（SAH）改变，以证实砷剂因竞争甲基而产生去甲基化作用；同时，从MDS频发突变的DNA甲基化相关基因DNMT3A、IDH1/IDH2和TET2的表达改变方面，阐释砷剂对DNA甲基化相关基因的影响。通过上述研究，进一步阐明砷剂治疗MDS疗效机理，为建立砷剂治疗MDS指导原则、明确砷剂治疗MDS适应亚型提供实验依据，这对提高MDS临床疗效，开辟砷剂治疗恶性血液病新领域具有重大意义。

2012-2016年国家自然科学基金课题“去甲基化- - 砷剂治疗骨髓增生异常综合征（MDS）机理研究”（81273931）已完成标书研究内容和研究目标。含砷中药青黄散对MDS异常高甲基化及低甲基化有双重调控作用，即以去甲基化为主，促甲基化为辅。青黄散对SAM-SAH-HCY循环圈存在影响，青黄散对DNMT1表达量的影响导致了SAM向SAH的进一步代谢减弱，结果使SAM向DNA提供的甲基基团减少，并非我们原先设想的砷剂解毒代谢过程中竞争甲基，从而产生去甲基化作用。本研究初步明确了含砷中药治疗MDS的作用机理，为临床治疗提供了一定的理论依据。含砷中药对MDS异常高甲基化及低甲基化的双重调控作用的深层次机制仍需要进一步研究。