Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, China.
Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, China.
Exp Cell Res. 2018 Apr 15;365(2):185-193. doi: 10.1016/j.yexcr.2018.02.036. Epub 2018 Mar 6.
Acute myeloid leukemia (AML) is a highly heterogeneous disease, with biologically and prognostically different subtypes. Although a growing number of distinct AML subsets have been increasingly characterized, patient management has remained disappointingly uniform. The molecular mechanism underlying AML needs to be further investigated. Here we identify IRF9 as a negative regulator of human AML. We show that IRF9 mRNA and protein levels are down-regulated in human AML samples compared with samples from healthy donors. IRF9 knockdown promotes proliferation, colony formation and survival of OCI/AML-2 and OCI/AML-3 cells, whereas IRF9 overexpression obtains oppose results. Mechanism analysis shows that IRF9 binds SIRT1 promoter and represses SIRT1 expression in OCI/AML-2 and OCI/AML-3 cells. In AML samples, the expression of SIRT1 is up-regulated and negatively correlated with IRF9 level. IRF9 also increases the acetylation of p53, a deacetylation substrate of SIRT1, and promotes the expression of p53 target genes. Knockdown of p53 blocks the effects of IRF9 on cell survival and growth in vitro. These findings provide evidence that IRF9 serves as an important regulator in human AML by repressing SIRT1-p53 pathway and that IRF9 may be a potential target for AML treatment.
急性髓系白血病（AML）是一种高度异质性的疾病，具有生物学和预后不同的亚型。尽管越来越多的不同 AML 亚群已经被逐渐确定，但患者的管理仍然令人失望地缺乏多样性。AML 的分子机制需要进一步研究。在这里，我们确定 IRF9 是人类 AML 的负调控因子。我们表明，与健康供体样本相比，IRF9 mRNA 和蛋白水平在人类 AML 样本中下调。IRF9 敲低促进了 OCI/AML-2 和 OCI/AML-3 细胞的增殖、集落形成和存活，而 IRF9 过表达则获得了相反的结果。机制分析表明，IRF9 结合 SIRT1 启动子并抑制 OCI/AML-2 和 OCI/AML-3 细胞中的 SIRT1 表达。在 AML 样本中，SIRT1 的表达上调，并与 IRF9 水平呈负相关。IRF9 还增加了 SIRT1 的去乙酰化底物 p53 的乙酰化，并促进了 p53 靶基因的表达。p53 的敲低阻止了 IRF9 对体外细胞存活和生长的影响。这些发现提供了证据，表明 IRF9 通过抑制 SIRT1-p53 通路在人类 AML 中充当重要调节剂，并且 IRF9 可能是 AML 治疗的潜在靶点。
