Ik6是抑癌基因Ikaros的一种显性负向亚型，申请人曾报道其异常增高与儿童B-ALL预后不良密切相关，并在体外过表达模型中证实Ik6基因能通过抗凋亡作用促进白血病细胞增殖和耐药，但潜在的分子机制尚未明确。国外有关研究发现，PI3K-Akt-FOXO1信号通路可通过影响Ikaros表达来调控B细胞的成熟及凋亡，从而参与白血病的发生、发展及耐药。为初探Ik6基因与该通路的关系，申请人对已收集的患儿骨髓标本进行检测，结果发现Ik6阳性组中Akt异常活化且磷酸化FOXO1呈高表达，由此推测Ik6可能参与Akt-FOXO1通路发挥抗凋亡作用。在本项目中我们拟构建Ik6沉默的体内外模型进一步验证Ik6基因对儿童B-ALL细胞凋亡的影响；通过体内外实验检测Ik6与Akt-FOXO1凋亡通路中有关信号分子表达及活性的关系以阐明Ik6抗凋亡的精确机制，为Ik6阳性B-ALL患儿的治疗提供新途径。

Ik6 is the main dominant negative isoform of Ikaros. In the previous study, we have shown that Ik6 is related to the poor prognosis of childhood B-lineage acute lymphoblastic leukemia (B-ALL); overexpression of Ik6 can enhance the proliferation, anti-apoptosis and chemoresistance of leukemia cells, but the mechanism has not been clarified. It has recently been reported that PI3K-Akt-FOXO1 signaling can regulate the maturation and apoptosis of B lymphocytes by influencing the expression of Ikaros and promote the initiation and progression of leukemia and chemoresistance. To explore the relationship between Akt-FOXO1 signaling and Ik6 expression，we have collected samples and found that the phosphorylation of Akt and FOXO1 both were up-regulated in Ik6 positive patients. Therefore, we hypothesize that Ik6 participate in the Akt-FOXO1 signal pathway-mediated anti-apoptosis. In this proposal, we will continue to investigate the influence of Ik6 on cell apoptosis through setting up the B-ALL models in vitro and in vivo; explore the relationship between Ik6 expression and activation of Akt-FOXO1 signaling, and illustrate the accurate mechanism of anti-apoptosis of Ik6. This study will potentially provide a new way for the therapy of Ik6 positive B-ALL patients.