title: miRNA-mRNA integrative analysis in primary myelofibrosis CD34+ cells: role of miR-155/JARID2 axis in abnormal megakaryopoiesis.
abstract: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by megakaryocyte (MK) hyperplasia, bone marrow fibrosis, and abnormal stem cell trafficking. PMF may be associated with somatic mutations in JAK2, MPL, or CALR. Previous studies have shown that abnormal MKs play a central role in the pathophysiology of PMF. In this work, we studied both gene and microRNA (miRNA) expression profiles in CD34(+) cells from PMF patients. We identified several biomarkers and putative molecular targets such as FGR, LCN2, and OLFM4. By means of miRNA-gene expression integrative analysis, we found different regulatory networks involved in the dysregulation of transcriptional control and chromatin remodeling. In particular, we identified a network gathering several miRNAs with oncogenic potential (eg, miR-155-5p) and targeted genes whose abnormal function has been previously associated with myeloid neoplasms, including JARID2, NR4A3, CDC42, and HMGB3. Because the validation of miRNA-target interactions unveiled JARID2/miR-155-5p as the strongest relationship in the network, we studied the function of this axis in normal and PMF CD34(+) cells. We showed that JARID2 downregulation mediated by miR-155-5p overexpression leads to increased in vitro formation of CD41(+) MK precursors. These findings suggest that overexpression of miR-155-5p and the resulting downregulation of JARID2 may contribute to MK hyperplasia in PMF.
authors.affiliation: Centre for Regenerative Medicine, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy;
authors.forename: Ruggiero
authors.initials: R
authors.lastname: Norfo
authors.affiliation: Centre for Regenerative Medicine, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy;
authors.forename: Roberta
authors.initials: R
authors.lastname: Zini
authors.affiliation: Centre for Regenerative Medicine, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy;
authors.forename: Valentina
authors.initials: V
authors.lastname: Pennucci
authors.affiliation: Centre for Regenerative Medicine, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy;
authors.forename: Elisa
authors.initials: E
authors.lastname: Bianchi
authors.affiliation: Centre for Regenerative Medicine, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy;
authors.forename: Simona
authors.initials: S
authors.lastname: Salati
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy;
authors.forename: Paola
authors.initials: P
authors.lastname: Guglielmelli
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy;
authors.forename: Costanza
authors.initials: C
authors.lastname: Bogani
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy;
authors.forename: Tiziana
authors.initials: T
authors.lastname: Fanelli
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy;
authors.forename: Carmela
authors.initials: C
authors.lastname: Mannarelli
authors.affiliation: Center for the Study of Myelofibrosis, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo Foundation, Pavia, Italy;
authors.forename: Vittorio
authors.initials: V
authors.lastname: Rosti
authors.affiliation: Department of Hematology Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo Foundation and University of Pavia, Pavia, Italy;
authors.forename: Daniela
authors.initials: D
authors.lastname: Pietra
authors.affiliation: Hematology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy;
authors.forename: Silvia
authors.initials: S
authors.lastname: Salmoiraghi
authors.affiliation: Department of Biology, University of Padua, Padua, Italy; and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bisognin
authors.affiliation: Centre for Regenerative Medicine, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy;
authors.forename: Samantha
authors.initials: S
authors.lastname: Ruberti
authors.affiliation: Centre for Regenerative Medicine, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy;
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Rontauroli
authors.affiliation: Centre for Regenerative Medicine, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy;
authors.forename: Giorgia
authors.initials: G
authors.lastname: Sacchi
authors.affiliation: Centre for Regenerative Medicine, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy;
authors.forename: Zelia
authors.initials: Z
authors.lastname: Prudente
authors.affiliation: Center for the Study of Myelofibrosis, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo Foundation, Pavia, Italy;
authors.forename: Giovanni
authors.initials: G
authors.lastname: Barosi
authors.affiliation: Department of Hematology Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo Foundation and University of Pavia, Pavia, Italy;
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.affiliation: Hematology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy;
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rambaldi
authors.affiliation: Department of Biology, University of Padua, Padua, Italy; and.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bortoluzzi
authors.affiliation: Center for Genome Research, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Ferrari
authors.affiliation: Center for Genome Research, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Tagliafico
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy;
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Vannucchi
authors.affiliation: Centre for Regenerative Medicine, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy;
authors.forename: Rossella
authors.identifier: http://orcid.org/https://orcid.org/0000-0003-0660-6110
authors.initials: R
authors.lastname: Manfredini
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D020868:Gene Silencing; D006098:Granulocytes / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D055728:Primary Myelofibrosis / Q000235:genetics*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics*; D015203:Reproducibility of Results; D034061:Thrombopoiesis / Q000235:genetics
chemical_list: D018952:Antigens, CD34; C547777:JARID2 protein, human; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D063151:Polycomb Repressive Complex 2
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