miRNA-mRNA integrative analysis in primary myelofibrosis CD34+ cells unveils the role of miR-155/JARID2 axis in abnormal megakaryopoiesis.

Differential gene and miRNA expression analysis in PMF granulocytes identifies new biomarkers and putative therapeutic targets.Activation of miR-155/JARID2 axis in PMF CD34+ cells results in overproduction of megakaryocyte precursors. AbstractPrimary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by megakaryocyte 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 megakaryocytes 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 oncomiRs (e.g., miR-155-5p) and targeted genes whose abnormal function has been previously associated to myeloid neoplasms, including JARID2, NR4A3, CDC42, and HMGB3. Since 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+ megakaryocyte precursors. These findings suggest that overexpression of miR-155-5p and the resulting downregulation of JARID2 may contribute to megakaryocyte hyperplasia in PMF.