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Int. J. Mol. Sci. 2017, 18(1), 145; doi:10.3390/ijms18010145

Role of miR-34a-5p in Hematopoietic Progenitor Cells Proliferation and Fate Decision: Novel Insights into the Pathogenesis of Primary Myelofibrosis

1
Centre for Regenerative Medicine “Stefano Ferrari“, Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
2
CRIMM, Center for Research and Innovation for Myeloproliferative Neoplasms, AOU Careggi and Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
3
Center for Genome Research, University of Modena and Reggio Emilia, 41125 Modena, Italy
The AGIMM (AIRC Gruppo Italiano Malattie Mieloproliferative) investigators is provided in the Acknowledgments.
*
Authors to whom correspondence should be addressed.
Academic Editor: Martin Pichler
Received: 28 October 2016 / Revised: 5 January 2017 / Accepted: 6 January 2017 / Published: 13 January 2017
(This article belongs to the Collection Regulation by Non-Coding RNAs)
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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. View Full-Text
Keywords: miR-34a-5p; nuclear receptor subfamily 4, group A, member 2 (NR4A2); lymphoid enhancer-binding factor 1 (LEF1); MYB; hematopoetic progenitor cells; hematopoietic differentiation; megakaryopoiesis; primary myelofibrosis; myeloproliferative neoplasms; macrophage miR-34a-5p; nuclear receptor subfamily 4, group A, member 2 (NR4A2); lymphoid enhancer-binding factor 1 (LEF1); MYB; hematopoetic progenitor cells; hematopoietic differentiation; megakaryopoiesis; primary myelofibrosis; myeloproliferative neoplasms; macrophage
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Bianchi, E.; Ruberti, S.; Rontauroli, S.; Guglielmelli, P.; Salati, S.; Rossi, C.; Zini, R.; Tagliafico, E.; Vannucchi, A.M.; Manfredini, R. Role of miR-34a-5p in Hematopoietic Progenitor Cells Proliferation and Fate Decision: Novel Insights into the Pathogenesis of Primary Myelofibrosis. Int. J. Mol. Sci. 2017, 18, 145.

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