MUM1/IRF4在多发性骨髓瘤中对Th17细胞的调控及其机制研究

Multiple myeloma (MM) is a plasma cell dyscrasia characterized by the accumulation of malignant plasma cells within the bone marrow. Although in recent years, novel agents such as bortezomib, thalidomide and lenalidomide have greatly improved the prognosis in multiple myeloma, the disease remains largely incurable.Previous studies showed that the expression of MUM1/IRF4 was high in most patients with MM. Our preliminary experiments showed that over-expression of MUM1/IRF4 in MM cells induced MM cells markedly proliferation and the expression of IRF4 was associated with angiogenesis and resistance to bortezomib, suggesting that MUM1/IRF4 plays a crucial role in MM. However,the precise mechanisms of MUM1/IRF4 still need to be explored. Th17 cells have recently been identified as a new lineage of effector Th cells. The critical role of interleukin-17-producing marrow infiltrating lymphocytes (MILs) enhances osteoclast activation and mediates bone lesions in myeloma patients. Levels of cytokines that selectively induce and maintain the Th17 phenotype tightly correlated with the extent of bone disease in myeloma. MUM1/IRF4 plays an important role in inducing Th17 cells differentiation. Therefore, we put forward the hypothesis that MUM1/IRF4 plays roles in the pathogenesis, prognosis,angiogenesis and bortezomib-resistance of MM via regulating Th17 cells. To verify the hypothesis, we will investigate it from several levels of molecule，cell line ,animal model and clinical MM patients. This project aims to elucidate the molecular mechanisms on regulation of Th17 cells by MUM1/IRF4 from the new viewpoint, which will provide strong evidence for the choice of treatment regimens and target therapy.

虽然多发性骨髓瘤（MM）分子细胞遗传学研究及其针对性靶向治疗已取得较大进展，但迄今仍是不可治愈的疾病，需进一步明确MM发病中起关键作用的因子。已有研究证明大部分MM患者MUM1/IRF4高表达，而我们前期研究结果显示MUM1/IRF4高表达促进了MM瘤细胞的生长和增殖，且与耐药和血管新生有关。但其确切的作用机制还有待进一步探讨。Th17细胞是一种新型的效应T细胞，与MM免疫、细胞增殖、血管新生和骨病变有关，而MUM1/IRF4在Th17细胞分化中起重要作用。由此提出MUM1/IRF4可通过调控Th17细胞在MM发病、预后、血管新生及耐药中发挥作用的假说。本项目拟从分子、细胞、动物模型以及临床MM患者等多个层面对此假说进行研究。我们旨从一个全新的角度阐述MUM1/IRF4在MM发病、预后、血管新生及硼替佐米耐药中的分子机理，为MM治疗方案选择及靶向治疗提供新的思路。

虽然多发性骨髓瘤（MM）分子细胞遗传学研究及其针对性靶向治疗已取得较大进展，但迄今仍是不可治愈的疾病，需进一步明确MM发病中起关键作用的因子。MUM1/IRF4高表达促进了MM瘤细胞的生长和增殖，且与耐药和血管新生有关，Th17细胞是一种新型的效应T细胞，Th17细胞与MM免疫、细胞增殖、血管新生和骨病变有关，而MUM1/IRF4在Th17细胞分化中起重要作用。该课题采用MACS细胞分选、FISH、RT-PCR、RNA干扰、细胞转染、双荧光素酶报告系统、Western-Blot、流式细胞术和骨髓活检标本组织化学染色等技术进行了研究，结果显示：（1）明确了MUM1/IRF4的表达与临床分期相关，Ⅲ期的患者的IRF4表达水平显著高于疾病分期为Ⅰ期和Ⅱ期的患者。（2）MUM1/IRF4促进MM细胞增殖和抑制MM细胞凋亡。（3）MUM1/IRF4介导MM细胞对硼替佐米耐药，但是免疫调节剂（沙利度胺和来那度胺）敏感的指标。（4）MM患者外周血细胞中Th17细胞比例增高，血清中IL-17水平也增高。（5）初发MM患者Th17细胞比例及IL-17水平与MUM1/IRF4表达强度正相关。综上结果提示：MUM1/IRF4可通过介导Th17细胞在MM发病、预后及硼替佐米耐药中发挥作用，为MM治疗方案选择及靶向治疗提供新的思路。