转录因子MEF2C与Myc癌基因相互作用在Burkitt淋巴瘤发病中的意义及靶向干预研究

Burkitt lymphoma （BL）is germinal center B-cell-derived lymphoma with a highly aggressive course . The clinical presentation of BL is hyper-heterogeneity and often exhibits bulky disease - extranodal sites involvement (BL) or a leukemic phase (bone marrow involvement) and purely as leukemia with PB and BM involvement - acute lymphocytic leukemia - L3 . Most of BL cases have Myc translocation at 8q24 to IG heavy chain at 14q32 , ie . t(8;14) , resulting Myc/IGH fusion gene cooperates the pathogenesis of BL . Myc over-expression may promote cell proliferation and arrest cell differentiation . However , the pro-apoptotic properties of c-Myc must be counterbalanced by other survival signals . The fact that up to 10% of BL lack a demonstrable Myc translocation , but with up-regulated Myc expression , indicates other regulating factors including transcriptional factor activator or IIa histone deacetylases (HDACs) interact with Myc and cooperate the switch of BL lymphomagenesis . Our previous works showed that Myocyte enhancer factor 2C (MEF2C) -a transcriptional activator , exhibited an up-regulated expression on Burkitt lymphoma cell line (Raji cell line) , and MEF2C expression was paralleled to the Myc expression . We also found that CC1007 , a small molecular compound , which is able to target to the interaction of “MEF2C/HDACs” , inhibited Raji cell growth and induced apoptosis significantly on Raji cell . In the present study , we want to make further investigation : (1) To determine whether there is a interaction between MEF2C and Myc , or Myc and HDACs , and elucidate the mechanism of MEF2C/Myc interaction ; (2) To confirm the anti-BL effect of CC1007 in vitro and uncover the molecular mechanism of anti-BL activity for CC1007; (3) To set up human primary ALL-L3 xenograft NOD/SCID mouse model and observe the anti-leukemic activity of CC1007 ex vivo . Our project will provide an experiment evidences for a new molecular-targeted therapy on Burkitt lymphoma .

Burkitt淋巴瘤（BL）是一种具高度侵袭性B细胞淋巴瘤，大多具有特征性Myc/IGH基因重排。Myc基因过表达促使淋巴瘤细胞增殖，阻滞瘤细胞分化。但Myc基因的促凋亡活性意味着在BL存在驱动性增殖信号过表达以“对抗”这一作用；约10%的BL并不存在Myc/IGH重排，仍有Myc过表达，故可能存在其他转录因子与Myc相互作用，以“协同”操纵BL发病“驱动”开关。我们前期工作发现：BL细胞株（Raji）存在转录因子“肌细胞增强因子2C（MEF2C）”过表达，其表达量与Myc平行；用靶向“MEF2C/HDACs”小分子化合物—CC1007作用Raji细胞，可抑制细胞生长，诱导凋亡，并下调Myc基因表达。本项目欲进一步研究BL细胞是否存在MEF2C/Myc、Myc/HDACs相互作用及调控机制；并用CC1007干预BL细胞，体内外实验研究药物抗BL活性及机理；为BL分子靶向治疗提供依据。

伯基特淋巴瘤（Burkitt lymphoma，BL）是一种具有高度侵袭性的B细胞淋巴瘤，大多具有特征性的Myc/IGH基因重排和c-Myc过表达。c-Myc异常表达可能与转录因子-肌细胞增强因子2C（MEF2C）调控相关。BL细胞的高增殖潜能及凋亡耐受能力也与过度活化的JAK2/Stat3信号转导途径相关。本项目对BL细胞株Raji细胞系MEF2C基因表达进行了定量测定，结果显示Raji细胞及原代BL细胞（8例）均存在MEF2C mRNA高表达；对原代BL病理切片及Raji细胞系检测发现伯基特淋巴瘤病理标本和Raji细胞均存在p-JAK2及p-Stat3蛋白高表 达。通过免疫共沉淀技术及激光共聚焦技术，证明了MEF2C/c-Myc可形成复合物并存在相互作用。确定了JAK2抑制剂- TG101209体外抗Berkitt 淋巴瘤活性与药物抑制BL细胞增殖，促使淋巴瘤细胞分化以及诱导细胞凋亡有关； TG101209诱导细胞凋亡途径涉及线粒体凋亡途径。.TG101209体内抗BL活性已在人源性Burkitt淋巴瘤原代细胞异种移植鼠模型得到证实。上述研究结果为靶向JAK2/Stat3信号途径治疗Burkitt淋巴瘤开辟了新的治疗路径。