title: A data-driven network model of primary myelofibrosis: transcriptional and post-transcriptional alterations in CD34+ cells.
abstract: microRNAs (miRNAs) are relevant in the pathogenesis of primary myelofibrosis (PMF) but our understanding is limited to specific target genes and the overall systemic scenario islacking. By both knowledge-based and ab initio approaches for comparative analysis of CD34+ cells of PMF patients and healthy controls, we identified the deregulated pathways involving miRNAs and genes and new transcriptional and post-transcriptional regulatory circuits in PMF cells. These converge in a unique and integrated cellular process, in which the role of specific miRNAs is to wire, co-regulate and allow a fine crosstalk between the involved processes. The PMF pathway includes Akt signaling, linked to Rho GTPases, CDC42, PLD2, PTEN crosstalk with the hypoxia response and Calcium-linked cellular processes connected to cyclic AMP signaling. Nested on the depicted transcriptional scenario, predicted circuits are reported, opening new hypotheses. Links between miRNAs (miR-106a-5p, miR-20b-5p, miR-20a-5p, miR-17-5p, miR-19b-3p and let-7d-5p) and key transcription factors (MYCN, ATF, CEBPA, REL, IRF and FOXJ2) and their common target genes tantalizingly suggest new path to approach the disease. The study provides a global overview of transcriptional and post-transcriptional deregulations in PMF, and, unifying consolidated and predicted data, could be helpful to identify new combinatorial therapeutic strategy. Interactive PMF network model: http://compgen.bio.unipd.it/pmf-net/.
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Calura
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.|Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy.
authors.forename: S
authors.identifier: 0000-0001-6541-6590
authors.initials: S
authors.lastname: Pizzini
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Bisognin
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Coppe
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Sales
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Gaffo
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Fanelli
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Mannarelli
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Zini
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Norfo
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Pennucci
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Manfredini
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Romualdi
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Guglielmelli
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: A M
authors.initials: AM
authors.lastname: Vannucchi
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Bortoluzzi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D055728:Primary Myelofibrosis / Q000235:genetics* / Q000473:pathology; D012323:RNA Processing, Post-Transcriptional; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D018952:Antigens, CD34; D035683:MicroRNAs; D009363:Neoplasm Proteins