组蛋白H2B泛素化调控MLL白血病细胞对蛋白酶体抑制剂耐受性的分子机制

MLL白血病是一种常见的急性白血病，蛋白酶体抑制剂能特异地杀死MLL白血病细胞，但是患者最终不可避免地出现耐药和复发。近年研究发现，表观遗传修饰异常引起的药物耐受细胞是肿瘤细胞耐药的最初起源，但其调控机制尚不清楚。我们前期发现，蛋白酶体抑制剂诱导 MLL细胞发生表观遗传重编程，RNF20表达降低，组蛋白H2B泛素化（H2Bub）全局性丢失，导致细胞周期关键因子CyclinA1表达下调和可逆耐药细胞出现；去泛素化酶抑制剂能够恢复H2Bub和CyclinA1表达，逆转细胞耐药性。据此我们推测，RNF20介导的H2Bub通过调控CyclinA1表达促进MLL细胞产生药物耐受性。本项目将对H2Bub调控MLL细胞对蛋白酶体抑制剂耐受的表观遗传机制进行深入研究，揭示H2Bub对CyclinA1可逆表达的调控机理，针对性地干预MLL耐受细胞产生，为蛋白酶体抑制剂在MLL白血病中的转化应用打下基础。

MLL leukemia is a common acute leukemia with a very poor prognosis. Proteasome inhibitors specifically kill MLL leukemia cells, but resistance and relapse inevitably emergence in patients. Drug tolerance induced by abnormal epigenetic modifications has been considered to be the primary source of drug resistance in tumor cells, but its regulatory mechanism remains unclear. We previously found that proteasome inhibitors induced epigenetic reprogramming in MLL cells, resulting in decreased RNF20 expression, global loss of histone H2B ubiquitination (H2Bub), and down-regulation of Cyclin A1 expression, a key cell cycle regulator, leading to the generation of reversible drug resistance. Deubiquitinating enzyme inhibitors can restore the expression of H2Bub and Cyclin A1, and reverse drug resistance in MLL tolerant cells. Therefore, we speculate that RNF20-mediated H2Bub promotes the development of drug resistance in MLL leukemia by regulating the expression of Cyclin A1. This project will investigate the epigenetic regulation mechanism and therapy strategies of reversible tolerance in MLL leukemia cells, reveal the molecular mechanism of H2Bub on reversible expression of Cyclin A1, and specifically intervene the generation of MLL resistant cells. This study will provide a theoretical basis for the translational application of proteasome inhibitors in MLL leukemia.