miR34c重启衰老清除急性髓系白血病干细胞与机制研究

除少数预后良好的急性髓系白血病（AML）外,现有的治疗手段很难根治AML，其根本原因是不能清除白血病干细胞（LSCs）。我们长期的研究和他人的发现提示：（1）AML干细胞抵抗应激诱导衰老，是其干性维持的重要机制之一；（2）低水平的miR34c可能是AML干细胞衰老抵抗的原因之一；（3）上调的抗凋亡分子BCL-2和活性降低的代谢调节分子LKB1（liver kinase B1）可能具有诱导细胞衰老抵抗的新功能；随后的预实验发现：在AML干细胞中，miR34c恢复可抑制BCL-2表达并活化LKB1；因此我们推测：miR34c可能通过双向调节BCL-2和LKB1重启AML干细胞衰老，miR34c联合常规化疗可促进AML的根治。为此本项目拟研究：⑴ miR34c重启细胞衰老清除LSCs；⑵ miR34c双向调节BCL-2和LKB1诱导LSCs衰老的机制；⑶ miR34c联合常规化疗阻止白血病复发。

Despite considerable advances, acute myeloid leukemia (AML)remains incurable except for few patients with favourable prognosis factors,which is contributed to failure of leukemia stem cells(LSCs)eradication.The results from us and other groups suggest :(1)the resistance of AML stem cells against stress induced senescence could be one of reasons which retain LSCs stemness.(2)a lower level of miR34c could contribute to senescence resistance of AML stem cells.(3)the upregulation of BCL-2,a classic antiapoptotic molecule,and inactivation of liver kinase B1(LKB1),a known metabolism regulator,could induce cellular senescence resistance.Next,we found that miR34c inhibits the expression of BCL-2 but induces activation of LKB1 in LSCs.So,we guess that miR34c could induce AML stem cells senescence through the dual regulations of BCL-2 and LKB1,and the combination of miR34c and standard drugs could improve prognosis of patients with AML.Thus,in this project we will investigate :(1) whether miR34c could eradicate AML stem cells through restarting cellular senescence.(2) the mechanisms that miR34c induces LSCs senescence through the dual regulations of BCL-2 and LKB1.(3)inhibition of leukemia relapse through the combination of miR34c and standard drugs.