B-细胞特异因子PAX5与NF-κB通路Crosstalk的机制及其在多发性骨髓瘤中作用的研究

Transcription factor PAX5 is a lineage determining factor in B cell development through inhibiting non-B cell genes and inducing B cell development gens. Prevously reports have indicated that abnormal expression of PAX5 is oftenly found in multiple myelomas (MM). However, the functions and mechanisms of PAX5 in MM have never been reported yet. Our preliminary study has showed that the expression of PAX5 closely correlated with drug sensitivity in MM cells in both in vitro and in vivo experiments, particularly an significant drug resistance was observed with the first-line chemo drug Bortezomib and the other common used drugs. Molecular mechanism study demonstrated that PAX5 enhanced ubiquitination and phosphorylation on RIP2, and hereafter activation of NF-κB signaling. In this study, we propose to futher investigate the molecular mechanisms of PAX5-regulated RIP2 and NF-κB activation, and the role of PAX5 in drug resistance in MM. In parallel, the relationship between PAX5 expression and drug-resistance will be assessed from clinical data. The potential of using PAX5 as the indicator for diagnostic and treament for MM will be evaluated. We expected that the study will provide inside of the roles and mechanisms of PAX5 in MM, especially providing an additional biomarkers for clinical pratice on personalized medicin for treatment of MM .

B细胞特异转录因子PAX5，通过抑制非B系基因，激活B系特异性基因，调控和维持B细胞的定向分化发育，但在成熟浆细胞中PAX5表达消失。多发性骨髓瘤(MM)是恶性浆细胞癌，其中约30%仍表达PAX5，虽认为对肿瘤特性有重要作用，但其机制仍所知甚少。对MM原代细胞的初步研究发现，PAX5表达阳性与阴性相比，对目前临床一线化疗药物万苛等常用化疗药物表现出显著的抗性。小鼠荷瘤实验也证实，敲低PAX5可显著增强化疗药物敏感性。分子机制研究发现，PAX5可增强接头蛋白RIP2及下游NF-κB信号通路活化，提示PAX5可能通过与NF-κB通路相互作用，对临床一线化疗药物蛋白酶体抑制剂万珂产生抗性。据此，本研究拟深入揭示PAX5对RIP2-NF-κB信号通路相互作用的分子机制；及其在MM抗药性中的作用和机制。同时，扩大临床标本检测，评估PAX5在临床个体化治疗方案制定和疗效评价中的潜在意义。

课题运用生物化学、基因组学、细胞生物学及临床标本，全面深入的探讨和证实了B细胞分化因子在多发性骨髓中通过与NK-kB相互作用，影响NK-kB对下游基因靶基因的转录调控，促进多发性骨髓瘤细胞抗药能力。该研究揭示了多发性骨髓瘤特征分子PAX5的作用和机制，也证明了细胞特异性NF-kB结合蛋白决定了NF-kB信号通路在不同细胞和诱导条件下发挥了不同的功能作用。同时，本研究中还发现，淋巴细胞特异因子LSP-1（Lymphocytes Specific factor-1）与PAX5具有非常类似的通过与NF-kB相互作用，决定NK-kB细胞特异性功能的作用。另外，研究中还发现在树突状细胞中，BCAP分别与MyD88和PI3K相互作用，双向调节NK-kB和PI3K通路，动态调节和维持树突状细胞在免疫反应中的活化和稳态，由此描绘出一个简约的开关式细胞信号调控模型。...课题研究期间共发表SCI论文8篇，参加国内、外会议交流报告10余次，培养博士研究生4人、硕士研究生2人，全面完成了课题计划和任务。