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Critical role of miR-9 in myelopoiesis and EVI1-induced leukemogenesis
- Source :
- Proceedings of the National Academy of Sciences. 110:5594-5599
- Publication Year :
- 2013
- Publisher :
- Proceedings of the National Academy of Sciences, 2013.
-
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 ( FoxO s) 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.
- Subjects :
- Chromatin Immunoprecipitation
Myeloid
Biology
medicine.disease_cause
Colony-Forming Units Assay
Mice
Proto-Oncogenes
medicine
Animals
Humans
DNA Primers
Myelopoiesis
Multidisciplinary
Forkhead Box Protein O1
Reverse Transcriptase Polymerase Chain Reaction
Forkhead Box Protein O3
Neurogenesis
Forkhead Transcription Factors
Sequence Analysis, DNA
DNA Methylation
Biological Sciences
Flow Cytometry
Hematopoietic Stem Cells
MDS1 and EVI1 Complex Locus Protein
DNA-Binding Proteins
MicroRNAs
Haematopoiesis
HEK293 Cells
medicine.anatomical_structure
Gene Expression Regulation
DNA methylation
NIH 3T3 Cells
Cancer research
Ectopic expression
Stem cell
Carcinogenesis
Transcription Factors
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 110
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....c06f62bdc27eac1f5fac61b77ac43cd8