Primary myelofibrosis (PMF) is a clonal disorder of a hematopoietic stem cell included in the Philadelphia chromosome-negative chronic myeloproliferative disorders (MPD), together with polycythemia vera and essential thrombocythemia. The molecular mechanisms of these diseases were partially unravelled in 2005 with the identification of somatic gain-of-function of Janus kinase 2 (JAK2) and Thrombopoietin Receptor (MPL), after which many other mutated genes were found. Moreover, aberrant microRNA (miRNA) expression especially seems to add up to the molecular complexity of MPNs, as specific miRNA signatures discriminates MPN from normal donors. In order to have a comprehensive picture of miRNA deregulation and its relationship with differential gene expression in PMF cells, we obtained mRNA and miRNA profiles in the same CD34+ cells from 31 healthy donors and 42 PMF patients by means of Affymetrix technology. Several miRNAs involved in hematological malignancies or known as oncomirs were upregulated in PMF samples (hsa-miR-155-5p, miRNAs belonging to the miR-17-92 cluster), whereas other aberrantly expressed miRNAs have never been described in the hematological context (has-miR-335). Next, we carried out an in silico integrative analysis (IA) with Ingenuity Pathway Analysis software, which combines the computational predicted targets with the gene expression data to construct regulatory networks of the functional miRNA-mRNA interactions. Of note, IA identified a significant network in which the upregulated oncomirs miR-155-5p and miR29a-3p could explain the downregulation of targets whose lower expression was already described in myeloproliferative phenotypes (NR4A3, CDC42, HMGB3), and of the chromatin remodeler JARID2, which is frequently deleted in leukemic transformation of MPNs. This approach allowed the identification of different networks potentially involved in PMF onset and progression, highlighting the potential contribution of miRNAs to PMF pathogenesis.
Regulatory mRNA/microRNA networks in CD34+ cells from Primary Myelofibrosis / Pennucci, Valentina; Zini, Roberta; Norfo, Ruggiero; Ruberti, S.; Bianchi, Elisa; Salati, Simona; Gugliemelli, P.; Bisognin, A.; Rosti, V.; Pietra, D.; Ricci, C.; Fanelli, T.; Salmoiraghi, S.; Sacchi, G.; Prudente, Z.; Rontauroli, S.; Barosi, G.; Cazzola, M.; Bortoluzzi, S.; Tagliafico, E.; Vannucchi, A. M.; Ferrari, S.; Manfredini, R.. - STAMPA. - -:(2013), pp. 28-28. (Intervento presentato al convegno “MicroRNA: from basic research to therapeutic applications" tenutosi a Ferrara nel 16-17 Settembre 2013).
Regulatory mRNA/microRNA networks in CD34+ cells from Primary Myelofibrosis
PENNUCCI, VALENTINA;ZINI, Roberta;NORFO, RUGGIERO;BIANCHI, Elisa;SALATI, Simona;Tagliafico E.;
2013
Abstract
Primary myelofibrosis (PMF) is a clonal disorder of a hematopoietic stem cell included in the Philadelphia chromosome-negative chronic myeloproliferative disorders (MPD), together with polycythemia vera and essential thrombocythemia. The molecular mechanisms of these diseases were partially unravelled in 2005 with the identification of somatic gain-of-function of Janus kinase 2 (JAK2) and Thrombopoietin Receptor (MPL), after which many other mutated genes were found. Moreover, aberrant microRNA (miRNA) expression especially seems to add up to the molecular complexity of MPNs, as specific miRNA signatures discriminates MPN from normal donors. In order to have a comprehensive picture of miRNA deregulation and its relationship with differential gene expression in PMF cells, we obtained mRNA and miRNA profiles in the same CD34+ cells from 31 healthy donors and 42 PMF patients by means of Affymetrix technology. Several miRNAs involved in hematological malignancies or known as oncomirs were upregulated in PMF samples (hsa-miR-155-5p, miRNAs belonging to the miR-17-92 cluster), whereas other aberrantly expressed miRNAs have never been described in the hematological context (has-miR-335). Next, we carried out an in silico integrative analysis (IA) with Ingenuity Pathway Analysis software, which combines the computational predicted targets with the gene expression data to construct regulatory networks of the functional miRNA-mRNA interactions. Of note, IA identified a significant network in which the upregulated oncomirs miR-155-5p and miR29a-3p could explain the downregulation of targets whose lower expression was already described in myeloproliferative phenotypes (NR4A3, CDC42, HMGB3), and of the chromatin remodeler JARID2, which is frequently deleted in leukemic transformation of MPNs. This approach allowed the identification of different networks potentially involved in PMF onset and progression, highlighting the potential contribution of miRNAs to PMF pathogenesis.
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