title: The NF-κB p65/miR-23a-27a-24 cluster is a target for leukemia treatment.
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.
authors.affiliation: Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yong-Chang
authors.initials: YC
authors.lastname: Zhang
authors.affiliation: Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ye
authors.affiliation: Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) and Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chin
authors.affiliation: Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yu-Ning
authors.initials: YN
authors.lastname: Huang
authors.affiliation: Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Guo-Hui
authors.initials: GH
authors.lastname: Fu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001483:Base Sequence; D002454:Cell Differentiation / Q000502:physiology; D004920:Erythropoiesis; D057809:HEK293 Cells; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D012717:Sesquiterpenes / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D035683:MicroRNAs; D012717:Sesquiterpenes; D051996:Transcription Factor RelA; C002669:parthenolide
keywords: NF-κB p65; erythroid differentiation; leukemia; miR-23a-27a-24 cluster