骨髓增生异常综合征（MDS）是由于全能干细胞水平上的恶性变化导致的分化障碍的血液病。去甲基化药物治疗MDS病人可以提高存活率，但DNA甲基化发生的原因，以及去甲基化药物的作用机制并不清楚。申请人在前期工作中发现高危MDS的克隆细胞中转录因子TWIST1的表达异常增高，TWIST1通过与p53直接结合抑制细胞的凋亡。前期预实验结果表明在MDS细胞中抑制TWIST1的表达能降低 CpG岛上甲基化水平和其靶基因启动子区的去甲基化。因此，本项目提出假设：TWIST1 参与了MDS中DNA的甲基化修饰。本项目将通过研究TWIST1与DNA甲基化酶（Dnmt） 如何相互作用调节DNA甲基化，并影响与p53有关的细胞增殖及细胞凋亡通路，以理解MDS中TWIST1的高表达与其靶基因高水平甲基化的作用机理，解释临床上使用去甲基化药物取得较好疗效的分子机制，并为进一步提高临床疗效提供理论策略。

Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem/precursor cells characterized by ineffective hematopoiesis, generally presenting with single or multilineage cytopenia in peripheral blood. Demethylation therapy is commonly used for patients with Myelodysplastic Syndrome (MDS), although it is unclear the mechanism of DNA methylation and how the demethylation medicine effectively worked in MDS clonal cells. Our previous data have shown that CD34+ marrow cells in advanced MDS express high levels of TWIST1, a basic helix-loop-helix transcription factor that opposes p53 function. The preliminary data suggested that inhibition of TWIST1 is associated with DNA de-methylation in MDS cells. We hypothesize that TWIST1 plays a key role in modifying the epigenome in MDS cells. Thus, we proposed the investigation of correlation between TWIST1 and DNA Methyltransferase (Dnmt), and the role of TWIST1/Dnmt complex in p53 pathway to regulate cell proliferation and cell apoptosis in MDS cells. This proposal can explain the mechanism of highly expressed TWIST1 correlates with DNA methylation, and explain the molecular mechanism of disease responses in demethylated treated patients, and make a contribution to enhance the efficacy of clinical therapy.