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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Premanand, Kavitha Chen, Ping Ming, Ming Senyuk, Vitalyi Chen, Jianjun Liu, Yang Rowley, Janet D. Nucifora, Giuseppina Qian, Zhijian Zhang, Yunyuan Zhou, Lan |
| Description | Author Affiliation: Senyuk V ( Department of Medicine, and Cancer Research Center, University of Illinois, Chicago, IL 60621, USA.); |
| Abstract | MicroRNA-9 (miR-9) is emerging as a critical regulator of organ development and neurogenesis. It is also deregulated in several types of solid tumors; however, its role in hematopoiesis and leukemogenesis is not yet known. Here we show that miR-9 is detected in hematopoietic stem cells and hematopoietic progenitor cells, and that its expression increases during hematopoietic differentiation. Ectopic expression of miR-9 strongly accelerates terminal myelopoiesis and promotes apoptosis in vitro and in vivo. Conversely, in hematopoietic progenitor cells, the inhibition of miR-9 with a miRNA sponge blocks myelopoiesis. Ecotropic viral integration site 1 (EVI1), required for normal embryogenesis, is considered an oncogene because its inappropriate up-regulation induces malignant transformation in solid and hematopoietic cancers. Here we show that EVI1 binds to the promoter of miR-9-3, leading to DNA hypermethylation of the promoter and repression of miR-9. Moreover, miR-9 expression reverses a myeloid differentiation block that is induced by EVI1. Our findings indicate that EVI1, when inappropriately expressed, delays or blocks myeloid differentiation at least in part by DNA hypermethylation and down-regulation of miR-9. It was reported that Forkhead box class O genes (FoxOs) inhibit myeloid differentiation and prevent differentiation of leukemia-initiating cells. Here we identify both FoxO1 and FoxO3 as direct targets of miR-9 in hematopoietic cells and find that up-regulation of FoxO3 inhibits miR-9-induced myelopoiesis. These results reveal a unique role of miR-9 in myelopoiesis and in the pathogenesis of EVI1-induced myeloid neoplasms and provide insights into the epigenetic regulation of miR9 in tumorigenesis. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 14 |
| Volume Number | 110 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2013-04-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | DNA Methylation DNA-Binding Proteins Metabolism Gene Expression Regulation Genetics Hematopoietic Stem Cells MicroRNAs Myelopoiesis Physiology Transcription Factors Animals Chromatin Immunoprecipitation Colony-Forming Units Assay DNA Primers Flow Cytometry Forkhead Transcription Factors HEK293 Cells Mice NIH 3T3 Cells Proto-Oncogenes Reverse Transcriptase Polymerase Chain Reaction Sequence Analysis, DNA Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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