The NF-κB p65/miR-23a-27a-24 cluster is a target for leukemia treatment.
The NF-κB p65/miR-23a-27a-24 cluster is a target for leukemia treatment.
复制标题
NF-κB p65/miR-23a-27a-24 簇是白血病治疗的靶标
DOI：
10.18632/oncotarget.5591
复制
发表时间：
2015-10-20
期刊：
影响因子：
--
通讯作者：
Fu GH
中科院分区：
文献类型：
--
作者：
Zhang YC;Ye H;Zeng Z;Chin YE;Huang YN;Fu GH
p65是一种转录因子，参与许多生理和病理过程。在这里，我们报告说，p65强烈结合的miR-23 a-27 a-24簇启动子，以上调其表达。随着骨髓源性细胞体外分化为红细胞，p65/miR-23 a-27 a-24簇表达急剧增加，然后在红细胞出现之前下降，表明该簇与红系终末分化呈负相关。生物信息学和分子生物学实验证实，miR-23 a-27 a-24簇抑制红细胞蛋白质组的表达，并促进红白血病的进展。此外，在APL和AML细胞系以及白血病患者的有核外周血细胞中发现了高水平的p65/miR-23 a-27 a-24簇。此外，抗白血病药物显著抑制白血病细胞中p65/miR-23 a-27 a-24簇的表达。给予p65抑制剂孤雌激素显著改善了血液学和骨髓象指数，同时延长了红白血病小鼠的寿命。同时，这三种miRNAs在小鼠红白血病细胞中的稳定过表达增强了细胞恶性度。因此，我们的发现将p65/miR-23 a-27 a-24簇的新调控途径与红系蛋白质组联系起来，并为治疗白血病提供了一种适用的方法。
p65 is a transcription factor that is involved in many physiological and pathologic processes. Here we report that p65 strongly binds to the miR-23a-27a-24 cluster promoter to up-regulate its expression. As bone marrow-derived cells differentiate into red blood cells in vitro, p65/miR-23a-27a-24 cluster expression increases sharply and then declines before the appearance of red blood cells, suggesting that this cluster is negatively related to erythroid terminal differentiation. Bioinformatic and molecular biology experiments confirmed that the miR-23a-27a-24 cluster inhibited the expression of the erythroid proteome and contributed to erythroleukemia progression. In addition, high level of the p65/miR-23a-27a-24 cluster was found in APL and AML cell lines and in nucleated peripheral blood cells from leukemia patients. Furthermore, anti-leukemia drugs significantly inhibited the expression of the p65/miR-23a-27a-24 cluster in leukemia cells. Administration of the p65 inhibitor parthenolide significantly improved hematology and myelogram indices while prolonging the life span of erythroleukemia mice. Meanwhile, stable overexpression of these three miRNAs in mouse erythroleukemia cells enhanced cell malignancy. Our findings thus connect a novel regulation pathway of the p65/miR-23a-27a-24 cluster with the erythroid proteome and provide an applicable approach for treating leukemia.