miRNA-mRNA integrative analysis in primary myelofibrosis CD34+cells: Role of miR-155/JARID2 axis in abnormal megakaryopoiesis

Ruggiero Norfo, Roberta Zini, Valentina Pennucci, Elisa Bianchi, Simona Salati, Paola Guglielmelli, Costanza Bogani, Tiziana Fanelli, Carmela Mannarelli, Vittorio Rosti, Daniela Pietra, Silvia Salmoiraghi, Andrea Bisognin, Samantha Ruberti, Sebastiano Rontauroli, Giorgia Sacchi, Zelia Prudente, Giovanni Barosi, Mario Cazzola, Alessandro RambaldiStefania Bortoluzzi, Sergio Ferrari, Enrico Tagliafico, Alessandro M. Vannucchi, Rossella Manfredini

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)e21-e32
JournalBlood
Volume124
Issue number13
DOIs
Publication statusPublished - Sep 25 2014

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology
  • Medicine(all)

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    Norfo, R., Zini, R., Pennucci, V., Bianchi, E., Salati, S., Guglielmelli, P., Bogani, C., Fanelli, T., Mannarelli, C., Rosti, V., Pietra, D., Salmoiraghi, S., Bisognin, A., Ruberti, S., Rontauroli, S., Sacchi, G., Prudente, Z., Barosi, G., Cazzola, M., ... Manfredini, R. (2014). miRNA-mRNA integrative analysis in primary myelofibrosis CD34+cells: Role of miR-155/JARID2 axis in abnormal megakaryopoiesis. Blood, 124(13), e21-e32. https://doi.org/10.1182/blood-2013-12-544197