TY - JOUR
T1 - miRNA-mRNA integrative analysis in primary myelofibrosis CD34+cells
T2 - Role of miR-155/JARID2 axis in abnormal megakaryopoiesis
AU - Norfo, Ruggiero
AU - Zini, Roberta
AU - Pennucci, Valentina
AU - Bianchi, Elisa
AU - Salati, Simona
AU - Guglielmelli, Paola
AU - Bogani, Costanza
AU - Fanelli, Tiziana
AU - Mannarelli, Carmela
AU - Rosti, Vittorio
AU - Pietra, Daniela
AU - Salmoiraghi, Silvia
AU - Bisognin, Andrea
AU - Ruberti, Samantha
AU - Rontauroli, Sebastiano
AU - Sacchi, Giorgia
AU - Prudente, Zelia
AU - Barosi, Giovanni
AU - Cazzola, Mario
AU - Rambaldi, Alessandro
AU - Bortoluzzi, Stefania
AU - Ferrari, Sergio
AU - Tagliafico, Enrico
AU - Vannucchi, Alessandro M.
AU - Manfredini, Rossella
PY - 2014/9/25
Y1 - 2014/9/25
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2013-12-544197
DO - 10.1182/blood-2013-12-544197
M3 - Article
C2 - 25097177
AN - SCOPUS:84907487389
VL - 124
SP - e21-e32
JO - Blood
JF - Blood
SN - 0006-4971
IS - 13
ER -