miR-433 is aberrantly expressed in myeloproliferative neoplasms and suppresses hematopoietic cell growth and differentiation

Abstract

BCR-ABL-negative myeloproliferative neoplasms (MPNs) are most frequently characterized by the JAK2V617F gain-of-function mutation, but several studies showed that JAK2V617F may not be the initiating event in MPN development, and recent publications indicate that additional alterations such as chromatin modification and microRNA (miRNA) deregulation may have an important role in MPN pathogenesis. Here we report that 61 miRNAs were significantly deregulated in CD34+ cells from MPN patients compared with controls (P<0.01). Global miRNA analysis also revealed that polycythemia vera (JAKV617F) and essential thrombocythemia (JAK2 wild type) patients have significantly different miRNA expression profiles from each other. Among the deregulated miRNAs, expression of miR-134, -214 and -433 was not affected by changes in JAK2 activity, suggesting that additional signaling pathways are responsible for the deregulation of these miRNAs in MPN. Despite its upregulation in MPN CD34+ and during normal erythropoiesis, both overexpression and knockdown studies suggest that miR-433 negatively regulates CD34+ proliferation and differentiation ex vivo. Its novel target GBP2 is downregulated during normal erythropoiesis and regulates proliferation and erythroid differentiation in TF-1 cells, indicating that miR-433 negatively regulates hematopoietic cell proliferation and erythropoiesis by directly targeting GBP2.

MicroRNA-433 regulates apoptosis by targeting PDCD4 in human osteosarcoma cells

“…Previous reports have shown that miR-433 is aberrantly expressed in various cancers. For example, miR-433 was decreased in myeloproliferative neoplasms, and overexpression of miR-433 suppressed hematopoietic cell growth and differentiation by targeting GBP2 (10). The present study demonstrated that miR-433 was upregulated in osteosarcoma tissues compared with the adjacent normal tissues, and inhibited osteosarcoma apoptosis.…”

“…Overexpression of miR-433 downregulated thymidylate synthetase mRNA and protein expression and enhanced the sensitivity of HeLa cells to 5-fluorouracil (9). In a previous study, miR-433 expression was decreased in myeloproliferative neoplasms, and overexpression of miR-433 was shown to inhibit hematopoietic cell growth and differentiation by targeting guanylate binding protein 2 (GBP2) (10). However, the role of miR-433 in osteosarcoma cells remains unknown.…”

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

“…Conversely, we showed that miR-155-5p inhibition in PMF CD34 assessment of the expression levels of several DEGs in PMF granulocytes highlighted a number of possible disease markers, which might eventually become relevant for target therapy approaches, such as membrane protein-and kinase-coding genes. Because miRNAs were recently demonstrated to be deregulated in MPN cells, [15][16][17] interest of their involvement in pathogenetic mechanisms is progressively growing. However, most of the miRNA and mRNA expression studies performed to date have been conducted using terminally differentiated hematopoietic cells, namely granulocytes or MKs.…”

“…1 cells has been reported in only 2 studies, including a limited number of patients 17,18 ; therefore, our understanding of the involvement of miRNAs in MPN pathogenesis is still limited.…”

MicroRNA deregulation in polycythemia vera and essential thrombocythemia patients

“…Deregulated miRNA profiles have been reported in MPN patients during in vitro erythroid differentiation as well as in peripheral blood granulocytes, platelets, and reticulocytes [26,27]. Since the MPNs are stem cell disorders, comprehensive miRNA analysis in MPN stem cells is needed to further delineate their roles in MPN pathogenesis but so far there is only limited data in this area [26,[28][29][30].…”