HDACs/MEF2C/Nur77轴在多发性骨髓瘤发病中的作用及靶向干预研究

Multiple myeloma (MM) is a plasma cell malignancy characterized by clonal proliferation of plasma cells in the bone marrow. MM remains incurable because most patients will eventually relapse or become refractory to the treatments. Although the treatments have improved, the major problem in MM is the resistance to therapy. Recent data have indicated that orphan nuclear receptor Nur77 plays an important role in normal hematopoiesis and pathogenesis of hematological malignancies; Myocyte enhancer factor 2C (MEF2C) could sustainably inhibit the expression of Nur77, remove the pro-apoptotic effect of Nur77 and mediate the proliferation of tumor cells; Class IIa histone deacetylases (HDACs) interacts with MEF2C and regulates the transcriptional activity. Based on these clues, we propose in this project "HDACs /MEF2C / Nur77" axis is the key signal transduction pathway to the pathogenesis of MM. In view of this pathway, we treated MM cell lines and primary cells with CC1007, a small molecular compound, which may target the interaction of MEF2C/HDACs. The results show CC1007 could significantly inhibit the proliferation of myeloma cells, induce cell apoptosis and cell cycle arrest, along with downregulation of MEF2C and upregulation of Nur77. In the present project, we want to further study the antitumor activity and mechanism of CC1007 against MM cell lines and primary cells, explore the vital role of "HDACs /MEF2C / Nur77" axis in the pathogenesis of MM, and confirm the antitumor effect of CC1007 in vivo. Our results will open up a new path and present an alternative approach for MM treatment, especially for relapse or refractory MM.

多发性骨髓瘤（MM）是一种以骨髓中单克隆性浆细胞异常增生为特征的恶性肿瘤。大多数MM患者在治疗后最终进展为复发或难治阶段，其耐药现象成为目前MM治疗所面临的最大挑战。研究显示孤儿核受体Nur77参与了血液系统恶性肿瘤的发病过程；肌细胞增强因子2C（MEF2C）可抑制Nur77的表达，解除Nur77的促凋亡作用；Ⅱa 类HDACs可调控MEF2C的转录活性。基于以上线索，我们提出“HDACs/MEF2C/Nur77”轴是MM发病机制关键的信号转导通路。前期研究结果显示CC1007—一种靶向HDACs/MEF2C的小分子化合物，具有显著的抗骨髓瘤活性，并伴随着MEF2C下调及Nur77上调。本项目欲阐明“HDACs/MEF2C/Nur77”轴在MM发病中的作用及调控机制，并用CC1007干预MM细胞，体内外实验研究药物抗MM活性及机理，为MM尤其是复发难治型的治疗提供新的策略。