Dataset Information

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

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.

SUBMITTER: Bianchi E

PROVIDER: S-EPMC5297778 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Bianchi Elisa E Ruberti Samantha S Rontauroli Sebastiano S Guglielmelli Paola P Salati Simona S Rossi Chiara C Zini Roberta R Tagliafico Enrico E Vannucchi Alessandro Maria AM Manfredini Rossella R

International journal of molecular sciences 20170113 1

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 ...[more]

PMID: 28098757

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Project description:Hemopoiesis entails a series of hierarchically organized events that proceed throughout cell specification and terminates with cell differentiation. Commitment needs the transcription factors effort that, in concert with microRNAs, drives cell fate specification, answering to promiscuous patterns of gene expression by turning on lineage-specific genes and repressing alternate lineage transcripts. Therefore microRNAs and mRNAs cooperate to direct cell fate decisions. We obtained microRNAs profiles from human CD34+ hemopoietic progenitor cells and in-vitro differentiated erythroblasts, megakaryoblasts, monoblasts and myeloblasts precursors and we analyzed them together with the gene expression profiles of the same populations. We found that for most part of microRNAs specifically up-regulated in one single cell progeny an inverse correlation between microRNAs and down-regulated putative targets expression levels occurs. We chose hsa-mir-299-5p as a model to get further insights into the possible biological relevance of this microRNAs-mRNAs expression integrated analytical approach and we asked if the forced expression of a single lineage-specific microRNA is able to control the cell fate of CD34+ progenitors grown in multilineage culture conditions. Gain and loss of-function experiments established that mir-299-5p regulates hemopoietic progenitors fate modulating reciprocally megakaryocytic-granulocytic versus erythroid-monocytic differentiation and has at least two genuine targets, the transcription factors CTCF and SOX4. CD34+ hematopoietic progenitor cells were transfected with the Amaxa Nucleofector Device, using the Human CD34 Cell Nucleofection Kit, accordingly to the manufacturer’s instructions (Amaxa Biosystem, Cologne, Germany), and 5µg of either the Pre-miR miRNA Precursor Molecule—Negative Control # 1 (NC1) or the hsa-mir-299-5p Pre-miR miRNA Precursor Molecule (299-5p) (Ambion, Austin, TX, USA) and pulsed with the program U-008. The dataset is composed of three independent paired experiment of 299-5p gain of-function (three hsa-299-5p Pre-miR miRNA Precursor Molecule nucleoporated samples and three paired Pre-miR miRNA Precursor Molecule—Negative Control # 1 transfected ones).

Dataset Information

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

Publications

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

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