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Critical role of miR-9 in myelopoiesis and EVI1-induced leukemogenesis.

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 hematopoi... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America April 2, 2013, Vol.110(14), pp.5594-5599
Main Author: Senyuk, Vitalyi
Other Authors: Zhang, Yunyuan , Liu, Yang , Ming, Ming , Premanand, Kavitha , Zhou, Lan , Chen, Ping , Chen, Jianjun , Rowley, Janet D , Nucifora, Giuseppina , Qian, Zhijian
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1302645110
Link: http://search.proquest.com/docview/1323794763/?pq-origsite=primo
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title: Critical role of miR-9 in myelopoiesis and EVI1-induced leukemogenesis.
format: Article
creator:
  • Senyuk, Vitalyi
  • Zhang, Yunyuan
  • Liu, Yang
  • Ming, Ming
  • Premanand, Kavitha
  • Zhou, Lan
  • Chen, Ping
  • Chen, Jianjun
  • Rowley, Janet D
  • Nucifora, Giuseppina
  • Qian, Zhijian
subjects:
  • Animals–Genetics
  • Chromatin Immunoprecipitation–Metabolism
  • Colony-Forming Units Assay–Metabolism
  • DNA Methylation–Genetics
  • DNA Primers–Metabolism
  • DNA-Binding Proteins–Metabolism
  • Flow Cytometry–Genetics
  • Forkhead Box Protein O1–Physiology
  • Forkhead Box Protein O3–Metabolism
  • Forkhead Transcription Factors–Metabolism
  • Gene Expression Regulation–Metabolism
  • Hek293 Cells–Metabolism
  • Hematopoietic Stem Cells–Metabolism
  • Humans–Metabolism
  • Mds1 and Evi1 Complex Locus Protein–Metabolism
  • Mice–Metabolism
  • Micrornas–Metabolism
  • Myelopoiesis–Metabolism
  • NIH 3t3 Cells–Metabolism
  • Proto-Oncogenes–Metabolism
  • Reverse Transcriptase Polymerase Chain Reaction–Metabolism
  • Sequence Analysis, DNA–Metabolism
  • Transcription Factors–Metabolism
  • DNA Primers
  • DNA-Binding Proteins
  • Foxo1 Protein, Human
  • Foxo3 Protein, Human
  • Forkhead Box Protein O1
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Mds1 and Evi1 Complex Locus Protein
  • Mecom Protein, Human
  • Mirn92 Microrna, Human
  • Micrornas
  • Transcription Factors
ispartof: Proceedings of the National Academy of Sciences of the United States of America, April 2, 2013, Vol.110(14), pp.5594-5599
description: 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.
language: eng
source:
identifier: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1302645110
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleCritical role of miR-9 in myelopoiesis and EVI1-induced leukemogenesis.
creatorSenyuk, Vitalyi ; Zhang, Yunyuan ; Liu, Yang ; Ming, Ming ; Premanand, Kavitha ; Zhou, Lan ; Chen, Ping ; Chen, Jianjun ; Rowley, Janet D ; Nucifora, Giuseppina ; Qian, Zhijian
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ispartofProceedings of the National Academy of Sciences of the United States of America, April 2, 2013, Vol.110(14), pp.5594-5599
identifierE-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1302645110
subjectAnimals–Genetics ; Chromatin Immunoprecipitation–Metabolism ; Colony-Forming Units Assay–Metabolism ; DNA Methylation–Genetics ; DNA Primers–Metabolism ; DNA-Binding Proteins–Metabolism ; Flow Cytometry–Genetics ; Forkhead Box Protein O1–Physiology ; Forkhead Box Protein O3–Metabolism ; Forkhead Transcription Factors–Metabolism ; Gene Expression Regulation–Metabolism ; Hek293 Cells–Metabolism ; Hematopoietic Stem Cells–Metabolism ; Humans–Metabolism ; Mds1 and Evi1 Complex Locus Protein–Metabolism ; Mice–Metabolism ; Micrornas–Metabolism ; Myelopoiesis–Metabolism ; NIH 3t3 Cells–Metabolism ; Proto-Oncogenes–Metabolism ; Reverse Transcriptase Polymerase Chain Reaction–Metabolism ; Sequence Analysis, DNA–Metabolism ; Transcription Factors–Metabolism ; DNA Primers ; DNA-Binding Proteins ; Foxo1 Protein, Human ; Foxo3 Protein, Human ; Forkhead Box Protein O1 ; Forkhead Box Protein O3 ; Forkhead Transcription Factors ; Mds1 and Evi1 Complex Locus Protein ; Mecom Protein, Human ; Mirn92 Microrna, Human ; Micrornas ; Transcription Factors
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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.

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titleCritical role of miR-9 in myelopoiesis and EVI1-induced leukemogenesis.
authorSenyuk, Vitalyi ; Zhang, Yunyuan ; Liu, Yang ; Ming, Ming ; Premanand, Kavitha ; Zhou, Lan ; Chen, Ping ; Chen, Jianjun ; Rowley, Janet D ; Nucifora, Giuseppina ; Qian, Zhijian
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