Yang X, Xing H Y, Tang K J, Tian Z, Rao Q, Wang M, Wang J X
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China Yang Xue is working at the Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai 200030, China.
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
Zhonghua Xue Ye Xue Za Zhi. 2022 May 14;43(5):370-375. doi: 10.3760/cma.j.issn.0253-2727.2022.05.004.
To investigate the prognostic significance of interferon regulatory factor 9 (IRF9) expression and identify its role as a potential therapeutic target in acute promyelocytic leukemia (APL) . The gene expression profile and survival data applied in the bioinformatic analysis were obtained from The Cancer Genome Atlas and Beat acute myeloid leukemia (AML) cohorts. A dox-induced lentiviral system was used to induce the expression of PML-RARα (PR) in U937 cells, and the expression level of IRF9 in U937 cells treated with or without ATRA was examined. We then induced the expression of IRF9 in NB4, a promyelocytic leukemia cell line. In vitro studies focused on leukemic phenotypes triggered by IRF9 expression. ①Bioinformatic analysis of the public database demonstrated the lowest expression of IRF9 in APL among all subtypes of AML, with lower expression associated with worse prognosis. ②We successfully established a PR-expression-inducible U937 cell line and found that IRF9 was downregulated by the PR fusion gene in APL, with undetectable expression in NB4 promyelocytic cells. ③An IRF9-inducible NB4 cell line was successfully established. The inducible expression of IRF9 promoted the differentiation of NB4 cells and had a synergistic effect with lower doses of ATRA. In addition, the inducible expression of IRF9 significantly reduced the colony formation capacity of NB4 cells. In this study, we found that the inducible expression of PR downregulates IRF9 and can be reversed by ATRA, suggesting a specific regulatory relationship between IRF9 and the PR fusion gene. The induction of IRF9 expression in NB4 cells can promote cell differentiation as well as reduce the colony forming ability of leukemia cells, implying an anti-leukemia effect for IRF9, which lays a biological foundation for IRF9 as a potential target for the treatment of APL.
探讨干扰素调节因子9（IRF9）表达的预后意义，并确定其作为急性早幼粒细胞白血病（APL）潜在治疗靶点的作用。生物信息学分析中使用的基因表达谱和生存数据来自癌症基因组图谱和击败急性髓系白血病（AML）队列。使用多西环素诱导的慢病毒系统在U937细胞中诱导PML-RARα（PR）的表达，并检测在有无全反式维甲酸（ATRA）处理的U937细胞中IRF9的表达水平。然后我们在早幼粒细胞白血病细胞系NB4中诱导IRF9的表达。体外研究聚焦于由IRF9表达引发的白血病表型。①对公共数据库的生物信息学分析表明，在AML的所有亚型中，IRF9在APL中的表达最低，表达较低与较差的预后相关。②我们成功建立了PR表达可诱导的U937细胞系，并发现IRF9在APL中被PR融合基因下调，在NB4早幼粒细胞中未检测到表达。③成功建立了IRF9可诱导的NB4细胞系。IRF9的可诱导表达促进了NB4细胞的分化，并与较低剂量的ATRA具有协同作用。此外，IRF9的可诱导表达显著降低了NB4细胞的集落形成能力。在本研究中，我们发现PR的可诱导表达下调IRF9，且可被ATRA逆转，提示IRF9与PR融合基因之间存在特定的调控关系。在NB4细胞中诱导IRF9表达可促进细胞分化并降低白血病细胞的集落形成能力，这意味着IRF9具有抗白血病作用，为IRF9作为APL治疗的潜在靶点奠定了生物学基础。
