Zhuang Haihui, Li Fenglin, Xu Yulian, Pei Renzhi, Chen Dong, Liu Xuhui, Li Shuangyue, Ye Peipei, Yuan Jiaojiao, Lian Jiaying, Lu Ying
Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, China.
Institute of Hematology, Ningbo University, Baizhang Road 251#, Ningbo, China.
Ann Hematol. 2023 May;102(5):1063-1072. doi: 10.1007/s00277-023-05156-y. Epub 2023 Mar 23.
The transcription factor interferon regulatory factor 8 (IRF8), as a member of the IRF family, is essential for myeloid cell differentiation. However, the precise role of IRF8 in the pathogenesis of acute myeloid leukemia (AML) remains unknown. By using multivariate analysis, we discovered that high IRF8 expression was an independent poor predictor of overall survival (OS) in AML patients from our clinical follow-up study. The proliferation of three AML cell lines was significantly inhibited by shRNA-mediated knockdown of IRF8, owing to cell cycle S-phase arrest. Furthermore, we demonstrated that knocking down IRF8 could suppress the expression of CyclinA and CyclinB1, resulting in a shift in cell cycle distribution. Loss of IRF8 in AML cells decreased the expression of STAT3 and phosphor-STAT3 (pSTAT3), which are key factors in JAK/STAT signal pathway and are important for AML progression. Using a xenograft mouse model, we discovered the antiproliferative effect of losing IRF8 in vivo. In conclusion, this study found that IRF8 may play a prognostic factor and therapeutic target in AML.
转录因子干扰素调节因子8（IRF8）作为IRF家族的一员，对髓系细胞分化至关重要。然而，IRF8在急性髓系白血病（AML）发病机制中的具体作用仍不清楚。通过多变量分析，我们从临床随访研究中发现，高IRF8表达是AML患者总生存期（OS）的一个独立不良预测指标。由于细胞周期S期阻滞，shRNA介导的IRF8敲低显著抑制了三种AML细胞系的增殖。此外，我们证明敲低IRF8可抑制细胞周期蛋白A（CyclinA）和细胞周期蛋白B1（CyclinB1）的表达，导致细胞周期分布发生改变。AML细胞中IRF8的缺失降低了信号转导和转录激活因子3（STAT3）及磷酸化STAT3（pSTAT3）的表达，它们是JAK/STAT信号通路中的关键因子，对AML进展很重要。利用异种移植小鼠模型，我们发现体内缺失IRF8具有抗增殖作用。总之，本研究发现IRF8可能是AML的一个预后因素和治疗靶点。
