细胞外染色质对急性早幼粒细胞白血病的促凝血作用

We have first reported the location of phosphatidylserine and lactadherin in cells (Science 2008); the role of drug-induced PS exposure on acute promyelocytic leukemia (APL) cells in coagulation (J Thromb Haemost 2010), the contribution of lactadherin coordinated with phagocytosis to inhibiting procoagulant activity of APL cells (Blood 2012), and lactadherin functions as probe and anti-coagulant against PS (Thromb Haemost 2013). However, the etiology of primary hypercoagulability in APL before chemotherapy is unclear. In this study, extracellular DNA traps (ETs) of APL cells provide binding sites for clot factors. The process of cell death (ETosis) is vividly traced on releasing ETs and illustrating the coagulant dysfunction. To identify the new targets on coagulation pathway, we use DNase and antibodies against histone to block ETs, achieving the benefits of interdisciplinary subjects; the distribution of ETs/PS/tissue factor on APL cells and in clots, which is dynamically monitored for further quantifying the fibrin production. This study aims to elucidating the role of extracellular DNA on coagulant disorder in APL and establishing new therapeutic approaches for APL coagulopathy.

我们首次报道磷脂酰丝氨酸(PS)/乳粘素的细胞内外定位(Science 2008)、化疗诱导急性早幼粒细胞白血病(APL)细胞PS外翻致促凝(J Thromb Haemost 2010)、乳粘素和吞噬协同抑制APL细胞的促凝(Blood 2012)和两专利中的乳粘素作为PS探针和抗凝剂(Thromb Haemost 2013)。但治疗前APL高凝血机制不清。本项目以APL细胞为研究对象，细胞外染色质(ETs)为凝血因子提供支架，对APL细胞死亡(ETosis)释放ETs进行高分辨示踪，阐明化疗前ETosis产生的高凝机制；利用DNase/组蛋白抗体阻断ETs，明确其参与凝血途径的新靶点，实现由结构到功能研究的多学科交叉；原位、实时、动态监测ETs/PS/TF在APL细胞和血凝块中的分布和关系，定量纤维蛋白生成；从细胞和分子信号转导水平揭示APL自发性出凝血异常的病因并为其治疗提供新靶点。