多发性骨髓瘤（MM）获得性耐药的产生是临床治疗失败的主要原因，其中组蛋白修饰介导的表观遗传学调控被认为是“始动因素”之一，但参与耐药性产生的“组蛋白密码”未知。我们利用针对人类全部表观遗传基因的CRISPR/cas9 sgRNA文库筛选硼替佐米耐药的基因，发现敲除一种组蛋白甲基化识别蛋白HRP2引起MM细胞耐药性剧烈变化；而临床病人HRP2的水平与治疗后生存时间和预后具有正相关；在MM细胞中改变HRP2表达导致其对BTZ的敏感性改变；Co-IP发现HRP2复合体招募染色质修饰的分子，而且HRP2本身具有形成蛋白液-液相分离的特性。本项课题将从体内外实验探究MM耐药性发生时HRP2复合体的构成和对染色体构象和开放程度调控的机制和临床意义，并探索HRP2蛋白液-液相分离在MM耐药性产生中的作用。本研究旨在探索MM耐药性产生的始动因素，为深入了解MM的耐药性产生提供新的理论。

The chemotherapy induced multidrug resistance is one of the most important reason for the failure of Multiple Myeloma (MM) therapy in clinic， and chromatin modification mediated epigenetics regulation is believed to be one of the fundamental and initiative reason， however， the chromatin modification mechanisms， or the "histone code" involved in the generation of drug resistance is unknown. We used CRISPR / cas9 sgRNA library to screen bortezomib resistant genes， and found that knockout of HRP2， a histone methylation reader protein， caused severe changes in drug sensitivity of MM cells; the level of HRP2 in clinical patients was positively related to survival time and prognosis after treatment; the change of HRP2 expression in MM cells led to the change of sensitivity to BTZ; co-IP found that HRP2 complex recruited chromatin modified molecules， and HRP2 itself had the property of forming protein liquid-liquid separation. In this project，we will explore the composition of HRP2 complex and the mechanism by which HRP2 regulats the conformation and accessbility of chromosomes when MM drug resistance occurs from clinical significance， in vivo and in vitro experiments， and explore the role of HRP2 protein liquid-liquid separation in MM resistance..The purpose of our study is to understand the fundamental and underlying mechanisms governing the initiation of BTZ-induced drug resistance in MM cells， and benefits the overcoming of refractory and relapse of patients with MM in clinic.