NF-κB/COX-2信号通路在甲硫氨酸γ-裂解酶抗MLL白血病作用中的机制研究

The MLL-rearranged leukemia was chemotherapy resistant, and the prognosis of it was poor. The traditional drug treatments and bone marrow transplantation couldn't improve the prognosis. Therefore, it is very important to find the targeted drugs to treat the MLL-rearranged leukemia. In our earlier studies, we found that the activation of NF-κB/COX-2 signaling pathway was very important for the tumor growth and development and the drugs targeted NF-κB/COX-2 signaling pathway could kill tumor cells. In our preliminary experiments, we found that the expression of NF-κB and COX-2 in the MLL-rearranged leukemia were high. In addition, we found that the methionine gamma-lyase discovered by ourselves could inhibit the cell proliferation and decrease the expression of NF-κB and COX-2. However, whether the effects of methionine gamma-lyase on the MLL-rearranged leukemia were regulated by NF-κB/COX-2 signaling pathway or not, it remains unclear. In this study, we will study the effects of methionine gamma-lyase on the NF-κB/COX-2 signaling pathway, cell proliferation, cell cycle, cell apoptosis and leukemia cell growth in the animals, and the mechanism in the leukemia primary cells, cell lines and the animal models. That will identify the biological functions and molecular mechanisms of the methionine gamma-lyase as a new drug for MLL-rearranged leukemia. This program will provide theoretical and experimental basis for the methionine gamma-lyase as a new therepeutic target for MLL-rearranged leukemia via NF-κB/COX-2 signaling pathway.

MLL白血病易发生化疗耐药且预后差，传统化疗和骨髓移植不能改善其预后。因此，寻找靶向药物对治疗MLL白血病具有重要意义。我们前期研究发现NF-κB/COX-2信号通路的持续激活在肿瘤发生发展中起重要作用，靶向抑制该通路的药物可杀伤肿瘤细胞。在预实验中我们发现NF-κB及COX-2在MLL白血病中高表达，且我们自主研发的甲硫氨酸γ-裂解酶（MGL）能抑制MLL白血病细胞增殖及减少NF-κB、COX-2表达，但其是否通过抑制NF-κB/COX-2通路发挥抗MLL白血病作用，尚不清楚。为此，本项目拟在白血病原代细胞、细胞株及动物模型中，研究MGL调控NF-κB/COX-2通路影响细胞增殖、周期、凋亡和白血病体内生长等生物学功能及其机制，以明确MGL靶向治疗MLL白血病的作用及机制。本项目将为确立MGL靶向NF-κB/COX-2通路治疗MLL白血病提供更充分的理论和实验依据。

MLL白血病一般表现为白细胞计数高，其完全缓解率低，对常规化疗不敏感，且生存期短，预后较差，目前化疗和造血干细胞移植不足以改善MLL白血病患者的预后。因此，寻找靶向药物对治疗MLL白血病具有重要意义。我们前期研究发现NF-κB/COX-2信号通路的持续激活在肿瘤发生发展中起重要作用，靶向抑制该通路的药物可杀伤肿瘤细胞。通过实验我们发现NF-κB及COX-2在MLL白血病中高表达，且我们自主研发的甲硫氨酸γ-裂解酶（MGL）能抑制MLL阳性白血病细胞株及原代细胞增殖，促进其细胞凋亡，并减少NF-κB、COX-2表达，并进一步实验发现MGL抑制NF-kB结合COX-2基因启动子，从而抑制MLL下游信号通路表达。我们采用MLL白血病细胞株RS4-11建立裸鼠全身模型，给予MGL后发现裸鼠体重无明显下降，脾脏较对照组明显缩小。通过动物实验明确MGL在动物模型体内的抗MLL白血病作用。本项目通过在白血病原代细胞、细胞株及动物模型中，发现MGL通过NF-κB/COX-2通路抑制细胞增殖，促进细胞凋亡，并在动物体内验证MGL抗MLL白血病活性。本项目为确立MGL作为新型的NF-κB/COX-2信号通路抑制剂治疗临床MLL白血病患者提供更充分的理论和实验依据，这一新药的发现很有可能对治疗MLL白血病具有重要的临床意义及应用前景。