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Role of miR-34a-5p in Hematopoietic Progenitor Cells Proliferation and Fate Decision: Novel Insights into the Pathogenesis of Primary Myelofibrosis
- Source :
- International Journal of Molecular Sciences, International Journal of Molecular Sciences; Volume 18; Issue 1; Pages: 145, International Journal of Molecular Sciences, Vol 18, Iss 1, p 145 (2017)
- Publication Year :
- 2017
- Publisher :
- MDPI, 2017.
-
Abstract
- Primary Myelofibrosis (PMF) is a chronic Philadelphia-negative myeloproliferative neoplasm characterized by a skewed megakaryopoiesis and an overproduction of proinflammatory and profibrotic mediators that lead to the development of bone marrow (BM) fibrosis. Since we recently uncovered the upregulation of miR-34a-5p in PMF CD34+ hematopoietic progenitor cells (HPCs), in order to elucidate its role in PMF pathogenesis here we unravelled the effects of miR-34a-5p overexpression in HPCs. We showed that enforced expression of miR-34a-5p partially constrains proliferation and favours the megakaryocyte and monocyte/macrophage commitment of HPCs. Interestingly, we identified lymphoid enhancer-binding factor 1 (LEF1) and nuclear receptor subfamily 4, group A, member 2 (NR4A2) transcripts as miR-34a-5p-targets downregulated after miR-34a-5p overexpression in HPCs as well as in PMF CD34+ cells. Remarkably, the knockdown of NR4A2 in HPCs mimicked the antiproliferative effects of miR-34a-5p overexpression, while the silencing of LEF1 phenocopied the effects of miR-34a-5p overexpression on HPCs lineage choice, by favouring the megakaryocyte and monocyte/macrophage commitment. Collectively our data unravel the role of miR-34a-5p in HPCs fate decision and suggest that the increased expression of miR-34a-5p in PMF HPCs could be important for the skewing of megakaryopoiesis and the production of monocytes, that are key players in BM fibrosis in PMF patients.
- Subjects :
- 0301 basic medicine
nuclear receptor subfamily 4, group A, member 2 (NR4A2)
CD34
MYB
Antigens, CD34
Group A
Hematopoetic progenitor cells
Hematopoietic differentiation
Lymphoid enhancer-binding factor 1 (LEF1)
Macrophage
Megakaryopoiesis
Member 2 (NR4A2)
MiR-34a-5p
Myeloproliferative neoplasms
Nuclear receptor subfamily 4
Primary myelofibrosis
Catalysis
Molecular Biology
Computer Science Applications1707 Computer Vision and Pattern Recognition
Spectroscopy
Physical and Theoretical Chemistry
Organic Chemistry
Inorganic Chemistry
lcsh:Chemistry
Megakaryocyte
Nuclear Receptor Subfamily 4, Group A, Member 2
lcsh:QH301-705.5
Cell Differentiation
General Medicine
member 2 (NR4A2)
Computer Science Applications
medicine.anatomical_structure
embryonic structures
primary myelofibrosis
group A
hematopoietic differentiation
megakaryopoiesis
Megakaryocytes
nuclear receptor subfamily 4
Lymphoid Enhancer-Binding Factor 1
Down-Regulation
macrophage
Biology
hematopoetic progenitor cells
Models, Biological
Article
myeloproliferative neoplasms
Proinflammatory cytokine
03 medical and health sciences
Downregulation and upregulation
miR-34a-5p
medicine
Gene silencing
Humans
Cell Lineage
Gene Silencing
RNA, Messenger
Cell Proliferation
Monocyte
Gene Expression Profiling
Macrophages
Hematopoietic Stem Cells
Clone Cells
MicroRNAs
030104 developmental biology
lcsh:Biology (General)
lcsh:QD1-999
Primary Myelofibrosis
Case-Control Studies
Immunology
lymphoid enhancer-binding factor 1 (LEF1)
Cancer research
Bone marrow
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Volume :
- 18
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....5ec06ae33840ddef4ac9135dac01b5a7