白介素-6通过NF-κB介导MYC基因在HIV-/HHV8-Castleman病浆细胞恶性转化的机制

HIV-/HHV8-Castleman病（iMCD）为炎症性淋巴结增生性疾病，少数患者出现浆细胞恶性转化，其转化过程及机制不详且治疗困难。我们前期研究发现：iMCD患者及H2-L-hIL6转基因小鼠hIL-6升高伴浆细胞慢性增殖，恶性转化后MYC基因高表达。另外，有研究显示iMCD IL-6激活NF-κB信号通路，而NF-κB/MYC途径为浆细胞肿瘤的关键致病通路之一。故我们设想iMCD持续高水平的IL-6是通过NF-κB通路介导MYC基因的上调，导致浆细胞恶性转化。本项目以H2-L-hIL6转基因小鼠和患者为研究对象，从分子、细胞和组织等水平动态地研究IL-6/NF-κB/MYC轴在iMCD浆细胞恶性转化的机制。本研究将从IL-6/NF-κB/MYC轴促进浆细胞肿瘤转化这个新视角探讨iMCD浆细胞恶性转化的发生机制，为治疗和预防iMCD浆细胞恶性转化及浆细胞肿瘤的发生提供新的理论思路。

HIV-/HHV8- Castleman’s disease (iMCD) is an inflammatory lymphoproliferative disorder, in which malignant transformation of plasma cells occur in a subset of patient. However, the transformation process and the underlying mechanism are unknown. Our previous study found that in both iMCD patients and H2-L-hIL6 transgenic mice, the increased hIL-6 expression was associated with chronic proliferation of plasma cells, and the elevated MYC expression level past malignant transformation. In addition, studies have shown that in iMCD IL-6 activates the NF-κB signaling pathway, and the NF-κB / MYC axis is one of the key pathogenic pathways responsible for neoplastic plasma cell transformation. Therefore, we hypothesis that the sustained high level of IL-6 regulates the MYC gene overexpression via the NF-κB signaling pathway, which leads to malignant transformation of plasma cells in iMCD. In this study, we will investigate the mechanism of IL-6/NF-κB/MYC axis, that promotes the transformation of iMCD plasma cells in both H2-L-hIL6 transgenic mice and iMCD patients. This study aims to elucidate the mechanism of malignant transformation of iMCD plasma cells from the novel perspective of IL-6/NF-κB/MYC axis that potentially contributes to the transformation of plasma cell tumor, and provide new concepts for the prevention and treatment of malignant transformation of iMCD plasma cells and the progression of plasma cell tumors.