MicroRNA expression in maturing megakaryocytes

Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Blood (Impact Factor: 10.45). 12/2010; 116(23):e128-38. DOI: 10.1182/blood-2010-06-292920
Source: PubMed


MicroRNAs are small noncoding RNAs that regulate cellular development by interfering with mRNA stability and translation. We examined global microRNA expression during the differentiation of murine hematopoietic progenitors into megakaryocytes. Of 435 miRNAs analyzed, 13 were up-regulated and 81 were down-regulated. Many of these changes are consistent with miRNA profiling studies of human megakaryocytes and platelets, although new patterns also emerged. Among 7 conserved miRNAs that were up-regulated most strongly in murine megakaryocytes, 6 were also induced in the related erythroid lineage. MiR-146a was strongly up-regulated during mouse and human megakaryopoiesis but not erythropoiesis. However, overexpression of miR-146a in mouse bone marrow hematopoietic progenitor populations produced no detectable alterations in megakaryocyte development or platelet production in vivo or in colony assays. Our findings extend the repertoire of differentially regulated miRNAs during murine megakaryopoiesis and provide a useful new dataset for hematopoiesis research. In addition, we show that enforced hematopoietic expression of miR-146a has minimal effects on megakaryopoiesis. These results are compatible with prior studies indicating that miR-146a inhibits megakaryocyte production indirectly by suppressing inflammatory cytokine production from innate immune cells, but cast doubt on a different study, which suggests that this miRNA inhibits megakaryopoiesis cell-autonomously.

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    • "Later studies showed that miR-146a is expressed at relatively high levels in bone marrow (BM) CD34+ progenitors from healthy donors but is found at low levels in AML patients and even lower levels in monocytes, granulocytes, erythrocytes, and megakaryocytes from the peripheral blood or BM of healthy donors [7]. miR-146a is strongly upregulated during megakaryopoiesis in mice [8], and dysregulation of miR-146a has been found in APL cells following retinoic acid (RA) induction [9–12]. Our previous study confirmed the reduced expression of miR-146a in NB4 cells following treatment with ATRA [13]. "
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    ABSTRACT: Background: Although the curative rate for acute promyelocytic leukemia (APL) has been improved over decades, long-term prognosis is still poor. The genetic pathways that regulated cell lineage fate during the development of APL remain unclear. Methods: We investigated the correlations of miR-146a expression with its target gene Smad4 and the biological behaviors of NB4 cells. We also analyzed their expression in clinical samples from APL patients. Results: miR-146a influenced apoptosis and proliferation in NB4 cells. miR-146a influenced endogenous Smad4 protein levels in APL cells. miR-146a expression levels were positively correlated with white cell counts and PML/RARα fusion protein expression. miR-146a expression levels were negatively correlated with Smad4 protein and the helper T cell (Th)/the suppressor T cell (Ts) ratio in these patients. Conclusions: These findings indicated that miR-146a played an important role in the development of APL in part through the repression on Smad4 protein expression. miR-146a functioned as an oncogene and may be a novel prognostic biomarker in APL.
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    • "The impact of enforced expression of miR-146a on hematopoiesis is not as dramatic as miR-146a deletion. Overall, most studies have shown a minor impact of miR-146a overexpression on HSPC numbers and functions (Opalinska et al., 2010; Ghani et al., 2011; Starczynowski et al., 2011). It remains unclear whether enforced expression of miR-146a would impair myelopoiesis under stressed conditions. "
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    ABSTRACT: Regulation of hematopoiesis is controlled by microRNAs (miRNAs). In this review, we focus on miR-146a, and its role in regulating normal and malignant hematopoiesis. miR-146a is a negative regulator of immune cell activation by repressing two targets, TRAF6 and IRAK1. Genetic deletion of miR-146a confirmed a role of miR-146a during innate immune signaling as well as for hematopoietic stem cell function. miR-146a is also implicated in the pathogenesis of human myelodysplastic syndromes (MDSs) as it is located within a commonly deleted region on chromosome 5, and miR-146a-deficient mice exhibit features of an MDS-like disease. With new insight into miR-146a through genetic and expression analyses, we highlight and discuss the recent advances in the understanding of miR-146a in physiological hematopoiesis during steady-state and inflammation, as well as in MDS.
    Full-text · Article · Jul 2014 · Frontiers in Genetics
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    • "Earlier studies have shown that miRNAs control the MK development and release of platelets (Table 4). Opalinska et al. studied miRNA expression in murine system where they examined 435 miRNAs among them 13 were upregulated and 81 were downregulated [46]. Overexpressing the miR-155 in K562 cells decreased the differentiation of megakaryocyte and erythroid cells by regulating the targets Meis-1 and Ets-1 [44]. "
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    ABSTRACT: The production of different types of blood cells including their formation, development, and differentiation is collectively known as haematopoiesis. Blood cells are divided into three lineages erythriod (erythrocytes), lymphoid (B and T cells), and myeloid (granulocytes, megakaryocytes, and macrophages). Haematopoiesis is a complex process regulated by several mechanisms including microRNAs (miRNAs). miRNAs are small RNAs which regulate the expression of a number of genes involved in commitment and differentiation of hematopoietic stem cells. Evidence shows that miRNAs play an important role in haematopoiesis; for example, myeloid and erythroid differentiation is blocked by the overexpression of miR-15a. miR-221, miR-222, and miR-24 inhibit the erythropoiesis, whereas miR-150 plays a role in B and T cell differentiation. miR-146 and miR-10a are downregulated in megakaryopoiesis. Aberrant expression of miRNAs was observed in hematological malignancies including chronic myelogenous leukemia, chronic lymphocytic leukemia, multiple myelomas, and B cell lymphomas. In this review we have focused on discussing the role of miRNA in haematopoiesis.
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