title: 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.
authors.affiliation: Centre for Regenerative Medicine "Stefano Ferrari", Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy. elisa.bianchi@unimore.it.
authors.forename: Elisa
authors.initials: E
authors.lastname: Bianchi
authors.affiliation: Centre for Regenerative Medicine "Stefano Ferrari", Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy. samantha.ruberti@unimore.it.
authors.forename: Samantha
authors.initials: S
authors.lastname: Ruberti
authors.affiliation: Centre for Regenerative Medicine "Stefano Ferrari", Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy. sebastiano.rontauroli@unimore.it.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Rontauroli
authors.affiliation: CRIMM, Center for Research and Innovation for Myeloproliferative Neoplasms, AOU Careggi and Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy. paola.guglielmelli@unifi.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Guglielmelli
authors.affiliation: Centre for Regenerative Medicine "Stefano Ferrari", Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy. simona.salati@unimore.it.
authors.forename: Simona
authors.initials: S
authors.lastname: Salati
authors.affiliation: Centre for Regenerative Medicine "Stefano Ferrari", Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy. chiara.rossi@unimore.it.
authors.forename: Chiara
authors.initials: C
authors.lastname: Rossi
authors.affiliation: Centre for Regenerative Medicine "Stefano Ferrari", Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy. roberta.zini@unimore.it.
authors.forename: Roberta
authors.initials: R
authors.lastname: Zini
authors.affiliation: Center for Genome Research, University of Modena and Reggio Emilia, 41125 Modena, Italy. enrico.tagliafico@unimore.it.
authors.forename: Enrico
authors.initials: E
authors.lastname: Tagliafico
authors.affiliation: CRIMM, Center for Research and Innovation for Myeloproliferative Neoplasms, AOU Careggi and Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy. a.vannucchi@unifi.it.
authors.forename: Alessandro Maria
authors.initials: AM
authors.lastname: Vannucchi
authors.affiliation: Centre for Regenerative Medicine "Stefano Ferrari", Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy. rossella.manfredini@unimore.it.
authors.forename: Rossella
authors.initials: R
authors.lastname: Manfredini
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D016022:Case-Control Studies; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002999:Clone Cells; D015536:Down-Regulation / Q000235:genetics; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008533:Megakaryocytes / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000378:metabolism; D055728:Primary Myelofibrosis / Q000235:genetics / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D012333:RNA, Messenger
keywords: MYB; hematopoetic progenitor cells; hematopoietic differentiation; lymphoid enhancer-binding factor 1 (LEF1); macrophage; megakaryopoiesis; miR-34a-5p; myeloproliferative neoplasms; nuclear receptor subfamily 4, group A, member 2 (NR4A2); primary myelofibrosis