N-三甲基赖氨酸阻断急性B淋巴白血病beta-arrestin1与EZH2结合的表观遗传机制研究

中文摘要

英文摘要

Leukemia is the most common of childhood malignancies, and acute B lymphoblastic leukemia (B-ALL) is the major subtype of childhood leukemia. In recent years, although the treatment of B-ALL achieved a certain effect, there are still about 20-40% relapse rate for it. It is worldwide focus on looking for new treatment strategies for B-ALL, and the epigenetic target drug is becoming the focus of attention. Beta-arrestin1, one of multifunction cell scaffold proteins, could combine with multiple proteins to regulate cell functions. In our previous studies, we firstly found that beta-arrestin1 could bind with enhancer of zeste homolog 2 (EZH2), the key molecule for epigenetic regulation, to regulate gene methylation and leukemia progress of B-ALL initiating cells and chronic myeloid leukemia (CML). Here, we continue this preliminary study, to further explore the function role of N-trimethyl lysine, the small molecule that could block the key sites of beta-arrestin1 combination with EZH2, to affect gene methylation, histone acetylation and chromatin conformation epigenetic mechanism in vitro and in vivo models of B-ALL. This study will lay a theoretical and experimental basis for developing leukemia novel epigenetic drugs.

结题摘要

白血病是儿童恶性肿瘤之首，急性B淋巴细胞白血病(B-ALL)是儿童白血病的主要亚型。虽然近年来B-ALL治疗方法取得一定疗效，但仍约有20-40%的复发率，寻找新的治疗策略是世界各国研究重点，表观遗传靶点药物逐渐成为关注焦点。beta-arrestin1为具有多功能的细胞支架蛋白，能结合多分子调控细胞功能。课题组前期首次发现beta-arrestin1与表观遗传调控的关键分子EZH2结合，调节急性B-ALL起始细胞和慢性粒细胞白血病（CML）的基因甲基化，进而影响白血病进程。在本项目中延续前期研究，利用急性B淋巴细胞白血病体内外模型，深入探究能阻断beta-arrestin1与EZH2结合关键位点的小分子化合物N-三甲基赖氨酸作用B-ALL的功能，发现NTL仅在极高浓度时才对B-ALL细胞产生抑制作用，而此时NTL对于细胞的副作用也相应增加；中低浓度范围内NTL对B-ALL细胞促生长作用，且机制未明，故NTL不适于B-ALL细胞治疗。同时发现B-ALL病人中beta-arrestin1显著增高，且其可能与B-ALL LIC衰老减缓有关。进一步的体内外实验证明，敲低beta-arrestin1后减少B-ALL细胞P300与SP1结合在hTERT启动子上，降低hTERT转录与表达，从而通过hTERT-端粒酶-端粒轴影响B-ALL LIC的衰老进程。项目从体内外水平，首次阐释β-arrestin1调控B-ALL LIC细胞寿命的发病机制，为寻找新的药物靶点奠定基础。