NF-kB2信号在多发性骨髓瘤发生、发展中的作用

Multiple myeloma is a common, incurable malignant tumor of antibody-producing plasma cells. Recent studies provide genetic evidence for a critical role of NF-kB2 signaling in the pathogenesis of multiple myelomas. Approximately 20% of multiple myeloma tumors harbor mutations that result in constitutive activation of NF-kB2 signaling. Some of the mutations occur in the NF-kB2 gene, leading to the generation of C-terminally truncated NF-kB2 mutants that are constitutively active transcription factors. We have recently generated the first transgenic mouse line with targeted expression of a tumor-derived NF-kB2 mutant, p80HT, in lymphocytes. The mutant mice develop predominantly B cell-lineage lymphomas, with over half of them being plasma cell tumors that display key features of human multiple myeloma, including a marked increase in bone marrow plasma cell content, osteolytic bone lesions and diffuse osteoporosis. These findings provide direct evidence for a causal role of NF-kB2 mutation in the pathogenesis of plasma cell tumors including multiple myelomas. What is unknown is the molecular mechanism by which NF-kB2 mutation or constitutive activation promotes the tumor development. Based on our published and preliminary studies, we hypothesize that NF-kB2 mutants transactivate the genes that promote the proliferation, survival and development of plasma cells, leading to their accumulation and eventual neoplastic transformation. We will test this hypothesis in animal models and human multiple myeloma cell lines. In studies under AIM1, we will identify p80HT target genes that drive the development of plasma cell tumors in p80HT mice using microarray and chromatin immunoprecipitation in combination with tag sequencing. We will further verify a selected group of target genes for mediating the tumorigenic activity of p80HT in animal models and examine the underlying mechanisms. In studies under AIM 2, we will identify the target genes that link NF-kB2 signaling to the proliferation, survival, and tumorigenic activity of human multiple myeloma cells. Through these studies, we anticipate the uncovering of direct links between NF-kB2 signaling and the genes relevant to multiple myeloma pathogenesis, and of novel mechanisms for NF-kB2 signaling in promoting the development and proliferation of normal and malignant plasma cells. A molecular understanding of the oncogenic activity of NF-kB2 signaling in the genesis, proliferation, and survival of malignant plasma cells may suggest points of therapeutic intervention and facilitate the development of new drugs against human multiple myeloma.

多发性骨髓瘤(MM)是一种常见的，难以治愈的恶性浆细胞肿瘤。大约有20%的MM患者体内存在NF-kB突变体，NF-kB活性异常高表达。p80HT是NF-kB的遗传突变体,我们已经建立了p80HT转基因小鼠，产生的主要是B淋巴瘤，其中超过一半以上是浆细胞瘤，具有骨髓中浆细胞数量超过10%，溶骨性骨质病变，弥漫性骨质酥松等症状，和人的MM临床症状极其相似，针对p80HT展开的研究将为我们证实NF-kB突变体能引起浆细胞瘤（包括MM）病变提供了直接的证据。然而p80HT如何促进浆细胞瘤的分子机制还不清楚。根据我们前期的实验结果，本课题组将探寻p80HT促进MM发育的靶基因，研究它们如何协同p80HT促进细胞增生、抗凋亡和肿瘤形成。通过本课题的研究期望找到直接联系p80HT和MM的靶基因，建立新的只产生MM疾病的小鼠模型。为MM早期诊断、控制病变进程、药物筛选以及预后判断提供理论依据

恶性肿瘤的发病率和死亡率逐年升高，严重危害人类健康，深入研究肿瘤的发生机制，探索新的治疗策略具有重大意义。肿瘤疾病临床治疗过程中耐药性副作用，严重影响了患者的治愈率和生存时间，因此需要通过靶向特异性的靶基因，对患者个性化治疗，或者针对多种靶基因联合化疗，避免耐药性的发生，达到彻底治疗肿瘤的目的。首先在多发性骨髓瘤中我们分离到纯化的B淋巴细胞，基因芯片分析促进淋巴瘤发生的机理机制；人类多发性骨髓瘤细胞株中，STAT3抑制细胞的生长，诱导细胞的死亡；并且发现p80基因能够促进一类新的B220-CD19+B1细胞的产生。另一方面我们同时开展了其他肿瘤疾病的发生、发展的相关研究，寻找深入研究肿瘤的发生机制，阐明调控肿瘤发生发展的信号通路。结果发现Cyclin-D1,2, Blimp,Survivin, IL-10,15, 等基因异常表达，找到了肿瘤进展的信号通路，为疾病的靶向治疗提供理论依据；HOXC9通过DAPK1-Beclin1信号通路调控自噬的分子机制，为实现个性化的分子靶向精准治疗提供新靶标和新途径；在分子水平阐明了G9a 抑制剂调控自噬的机制，为通过抑制G9a 作为治疗癌症的策略提供了理论基础；TAZ通过与去乙酰化酶HDAC9结合并受其调控来促进肿瘤的发生与形成，而直接下调HDAC9的表达则会抑制肿瘤的生长；替加环素通过p21CIP1/Waf1信号通路抑制肿瘤的发展和转移。本项目针对肿瘤发生与形成的分子机制，调控肿瘤细胞增殖、分化及凋亡的信号通路开展研究，针对多个目标基因联合药物治疗，为探寻新的治疗策略提供了可能。