MM依然是一种不可治愈的恶性肿瘤，耐药是导致复发的重要原因。探明MM复发、耐药的分子机制，对提高MM疗效具有重要意义。课题组前期对MM患者细胞序贯基因表达谱分析发现PHF19在治疗后及复发时肿瘤耐药克隆中表达明显增高并具有临床预后意义。并且证实miRNA-15a/-16靶向调控PHF19表达，上调miRNA-15a/-16表达可抑制MM细胞增殖、提高药物敏感性。据此我们提出MM细胞低表达miRNA-15a/-16导致其靶基因PHF19表达增加，促进MM细胞增殖与耐药，导致患者生存期缩短，预后不良的科学假设。本研究拟从基因、蛋白水平，体外及体内实验等多层次探讨miRNA-15a/-16靶向调控PHF19以及PHF19促进MM细胞增殖和耐药的分子机制。并结合ChIP-seq等高通量检测方法，探明PHF19作用的关键信号通路及调控分子和表观遗传学修饰信息，为寻找新的治疗靶点提供理论及实验基础。

Although major progress has been made in the treatment of MM with an increase in median survival from 2.5 to 10 years over the last two decades, the large majority of the patients still relapse and ultimately die of their disease. This is due to the persistence of a drug-resistant subpopulation of MM cells even after intensive therapy with tandem autologous transplants and prolonged maintenance with the newer drugs. To achieve a cure for MM, a better understanding of the genetic makeup of these drug-resistant MM cells is required so that these cells can be specifically targeted. Our previous study of sequential analysis of gene expression profiles (GEP) of tumor cells in MM patients showed that PHF19 expression was significantly up-regulated in resistant tumor cell clones of pre-1st ASCT and relapse MM patients. Kaplan-Meier analyses showed that MM patients with higher expression of PHF19 had a significantly inferior PFS and OS. Our preliminary results also demonstrated that miRNA-15a/-16 had lower expression in MM cells. Dual luciferase reporter assay indicated that PHF19 was the target gene of miRNA-15a/-16. Up-regulation of miRNA-15a/-16 suppressed MM cells proliferation and promoted drug induced apoptosis. It is our hypothesis that PHF19 as a target gene of miRNA-15a/-16 promotes MM cells proliferation and drug-resistance. Therefore, this project will investigate the miRNA-15a/-16 mediates PHF19 functions of cell proliferation and drug resistance in MM. Combined with ChIP-seq and microarray high-throughput assay, Co-IP experiments, as well as 5TGM1 mouse MM model, the PHF19 key signaling pathways and the role of regulatory molecules and epigenetic modification of information will be clarified. The results will provide theoretical and experimental foundation for the search for new therapeutic targets in MM.