Abstract
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.
Highlights
Cell differentiation is a complex process that is tightly controlled by many cellular and molecular mechanisms [1, 2]
Unlike transcription factors, which are often absolutely required for specific genes, miRNAs may fine-tune gene expression by targeting a group of genes [31,32,33]
Www.impactjournals.com/oncotarget levels during normal erythropoiesis and its activation in different types of leukemia have been reported, the erythroid differentiation mechanisms involving this protein and how they relate to leukemia progression are poorly understood
Summary
Cell differentiation is a complex process that is tightly controlled by many cellular and molecular mechanisms [1, 2]. Previous studies have elucidated the molecular events that occur during erythroid differentiation [6], and the role of transcription factors such as GATA-1, FOG-1 and Tal-1 that act by regulating the expression of a set of target genes [7,8,9]. Overexpression of p65 reduced the amounts of functional nuclear factor erythroidderived 2 (NF-E2) proteins in K562 cells [11], suggesting that NF-κB expression is negatively correlated with erythroid differentiation. We show that p65 is a strong positive regulator of the miR-23a-27a-24 cluster. These miRNAs target the erythroid proteome establishing a p65/miR-23a-27a-24/erythroid proteome pathway, the regulation of which plays an essential role in erythropoiesis. High expression level of the p65/ miR-23a-27a-24 cluster is a vital pathogenesis factor of erythroleukemia and other types of leukemia
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