靶向抑制组蛋白H3K9me2/3选择性去除白血病细胞的机制研究

急性白血病是一类具有高度异质性的恶性克隆性增殖性血液肿瘤，寻找杀灭白血病细胞而不损伤正常造血干/祖细胞的方法，一直是急性白血病治疗中的关键问题。表观遗传的异常调控被认为是急性白血病的一个重要标志，H3K9me2/3是基因沉默的表观标志，本项目基于前期青年基金，运用二次重编程模型发现抑制H3K9me2/3能选择性去除白血病细胞并对正常造血干祖细胞影响较小。因此，我们提出靶向抑制H3K9me2/3，可能为选择性去除白血病细胞提供新的切入点。本研究以原代白血病小鼠模型为基础，明确白血病细胞与正常造血干祖细胞的本底H3K9me2/3调控差异，通过抑制H3K9me2/3，及干预SUV39H1/2、KDM3A明确对白血病细胞生物学功能及关键靶基因的影响，并通过人源化白血病小鼠模型结合单细胞组学，明确抑制H3K9me2/3对各群正常及异常造血细胞的差异性调控，为研发急性白血病新的诊治靶点奠定基础。

Acute leukemia is a type of malignant clonal proliferative hematological tumor with a high degree of heterogeneity. Finding ways to kill leukemia cells without damaging normal hematopoietic stem / progenitor cells has been a key issue in the treatment of acute leukemia. The abnormal regulation of epigenetics has been considered as an important sign of acute leukemia. H3K9me2 / 3 is an epigenetic sign of gene silencing. This project is based on the previous youth fund and used a secondary reprogramming model to find that inhibition of H3K9me2 / 3 can selectively elininate leukemia cells have little effect on normal hematopoietic stem and progenitor cells. Therefore, we propose that targeted inhibition of H3K9me2 / 3 may provide a new entry point for the selective removal of leukemia cells. This study is based on the primary leukemia mouse model to clarify the difference in background H3K9me2 / 3 regulation between leukemia cells and normal hematopoietic stem progenitor cells. By inhibiting H3K9me2 / 3 and intervening with SUV39H1/2 and KDM3A, the biological function of leukemia cells is clearly defined and the influence of key target genes, and through the humanized leukemia mouse model combined with single cell sequencing, clearly inhibit the differential regulation of H3K9me2 / 3 on various groups of normal and abnormal hematopoietic cells, and it is a new clinical diagnosis and treatment target for the development of acute leukemia.