混合谱系白血病AIF-1/NFκB介导的调控机制研究

研究发现AIF-1在非急淋M4，M5亚型特异高表达且在混合谱系白血病（MLL）细胞系中与NFκB通路相关基因表达正相关, 而AIF-1在MLL白血病中的作用机制尚不明确。因此，申请者提出AIF-1作为PU.1的靶基因参与NFκB通路的激活，从而介导MLL白血病发生的假说。本研究拟以MLL白血病中AIF-1特异高表达为切入点，开展细胞和小鼠模型水平的研究：1）通过降低和回补表达明确AIF-1在MLL白血病中的致病作用；2）研究AIF-1如何参与NFκB通路的调节，明确AIF-1是否直接作用于NFκB通路中的关键组分; 3）鉴定AIF-1相互作用蛋白结合转录组学分析对上述提出的假说进行修正和完善，建立以AIF-1为中心的MLL白血病核内外共同参与的调控网络。基于上述研究，将阐明AIF-1在MLL白血病中的致病机理，为确立AIF-1作为MLL白血病临床检测靶标和治疗靶点提供更充分的科学依据。

The role and further regulation mechanisms of AIF-1 in leukemia were not well established. Base on our preliminary results, we found that AIF-1 is highly expressed in FAB-M4, M5 subtypes and knockdown AIF-1 expression in MLL leukemia cells significantly down-regulated NFκB pathway related genes. We hypothesize that AIF-1 regulate the activity of NFκB pathway, as the target of PU.1, contributing MLL leukemogenesis. To clarify the hypothesis, initiated from the phenomenon that AIF-1 highly expression in FAB-M4, M5 subtypes, we are planning to perform the molecular and cell biology experiments complementary with mouse model to determine the role of AIF-1 in MLL leukemogenesis; The regulation mechanism between AIF-1 expression and NFκB activation in MLL leukemia. Finally, we ought to complete and revise the hypothesis via integrating the transcriptome and AIF-1 pull-down data. This proposal aim to establish the regulation network mediated by AIF-1 in MLL leukemia. The results of this study will help us in understanding of MLL leukemia oncogenesis and will provide new clues for testing and therapy targets of this specific leukemia.