AML1/ETO-FTO-IGFBP2轴在t(8;21)急性髓系白血病化疗耐药中的机理研究

t(8;21)急性髓系白血病（AML）的化疗耐药是一个复杂的过程，除遗传学外，表观遗传调控也起着重要的作用，但具体机制尚不明确。N6-methyladenosine(m6A)是mRNA上含量最多的动态可逆的化学修饰之一，参与了白血病细胞恶性克隆形成。前期研究证实：m6A去甲基化酶FTO受SPI1的调控，而SPI1又与AML1/ETO负相关；FTO在t(8;21)AML发挥了癌基因的作用，促进细胞存活和化疗耐药，且依赖其去甲基化酶活性；MeRIP-seq分析表明，IGFBP2是FTO的一个重要靶基因，很可能通过C-Myc和NF-kB导致了化疗耐药。据此，我们推测：SPI1介导了AML1/ETO对FTO的调控，而IGFBP2则介导了FTO的化疗耐药作用。阐明AML1/ETO-FTO-IGFBP2轴在t(8;21)AML化疗耐药中的调控机制，为白血病临床诊断、预后分层和治疗提供了新的手段和策略。

Chemotherapy resistance of t(8;21) acute myeloid leukemia (AML) is a multi-step process. Beside genetics abnormal, epigenetics changes play a crucial role in accelerating and synergistic effect on leukemia, and has became a hot spot in study and therapeutic at present, however, the detail mechanism of chemotherapy resistance remain unknown. N6-methyladenosine(m6A) is one of the most abundant dynamic reversible chemical modifications on mRNA, which may participate in hematopoietic stem/progenitor cell differentiation, leukemia cell malignant clone development. Our previous results and international peer has confirmed that expression levels of m6A “eraser”- FTO were elevated and had a positive correlation with those of fusion protein AML1/ETO, and play a specificity oncogenic role in t(8;21) AML. FTO can promote AML cells survival, invasion, and chemotherapy resistance, which depends on the de-methylation activity of FTO. Analysis of MeRIP-seq and RNA-seq shown that IGFBP2 is a vital target gene of FTO, and probably mediate chemotherapy resistance of AML cells by C-Myc and NF-kB signal pathways. In this proposal, we are going to clarify the complicated network of AML1/ETO-FTO-IGFBP2 axis in t(8;21) AML, laid a foundation for the mechanism of the occurrence and recurrence of AML, also provides a new angle of view for us to fully understand the complex gene regulation network, what’s more, provides a new method and strategy for clinical diagnosis, prognosis stratification and treatment of leukemia.