Transcriptional profiling of mouse wild type Lmo2 transgenic DN thymocytes, and wild type bone marrow
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Carolyn de Graaf
PROVIDER: E-TABM-860 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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2011-12-21 | E-TABM-1134 | biostudies-arrayexpress
Project description:Thrombopoietin (TPO) acting via its receptor Mpl is the major cytokine regulator of platelet number. To precisely define the role of specific hematopoietic cells in TPO dependent hematopoiesis, we generated mice that express the Mpl receptor normally on stem/progenitor cells but lack expression on megakaryocytes and platelets (MplPF4cre/PF4cre). MplPF4cre/PF4cre mice displayed profound megakaryocytosis and thrombocytosis with a remarkable expansion of megakaryocyte-committed and multipotential progenitor cells, the latter displaying biological responses and a gene expression signature indicative of chronic TPO over-stimulation as the underlying causative mechanism, despite a normal circulating TPO level. Thus, TPO signaling in megakaryocytes is dispensable for platelet production; its key role in control of platelet number is via generation and stimulation of the bipotential megakaryocyte precursors. Nevertheless, Mpl expression on megakaryocytes and platelets is essential to prevent megakaryocytosis and myeloproliferation by restricting the amount of TPO available to stimulate the production of megakaryocytes from the progenitor cell pool.
2014-06-10 | E-MTAB-2389 | biostudies-arrayexpress
Project description:Thrombopoietin (TPO), acting through its receptor Mpl, has two major physiological roles: ensuring production of sufficient platelets via stimulation of megakaryocyte production, and maintaining hematopoietic stem cell (HSC) quiescence. Mpl also controls circulating TPO concentration via receptor-mediated internalisation and degradation. We demonstrate that the megakaryocytosis and increased platelet mass in mice with mutations in the Myb or p300 genes causes reduced circulating TPO concentration and TPO starvation of the stem cell compartment, which is exacerbated because these cells additionally exhibit impaired responsiveness to TPO. Total RNA obtained from bone marrow Lineage- Sca-1+ c-Kit+ cells of mice that were mutant or knocked out for Myb, p300 or Mpl were compared to wild type samples. We have found that HSCs from MybPlt4/Plt4 and p300Plt6/Plt6 mice show altered expression of TPO-responsive genes, suggesting that TPO starvation is an important factor in the hematopoietic phenotypes observed in these mice .
2011-01-31 | E-TABM-1050 | biostudies-arrayexpress
Project description:Down syndrome (DS), with trisomy of chromosome 21 (HSA21), is the commonest human aneuploidy. Pre-leukemic myeloproliferative changes in DS fetal livers precedes the acquisition of GATA1 mutations, transient myeloproliferative disorder (DS-TMD) and acute megakaryocytic leukemia (DS-AMKL). Trisomy of the Erg gene is required for myeloproliferation in the Ts(1716)65Dn DS mouse model. We demonstrate here that genetic changes due trisomy of Erg lead to lineage priming of primitive and early multipotential progenitor cells in Ts(1716)65Dn mice, excess megakaryocyte-erythroid progenitors, and malignant myeloproliferation. Correlation of gene expression changes caused by Erg trisomy in Ts(1716)65Dn multilineage progenitor cells with those associated with trisomy 21 in human DS HSCs support a role for ERG as a regulator of hematopoietic lineage potential, trisomy of which drives pre-leukemic changes in DS fetal livers that predispose to subsequent DS-TMD and DS-AMKL.
2015-04-15 | E-MTAB-2574 | biostudies-arrayexpress
Project description:Single cell suspensions of E10.5 yolk sac cells and E13.5 fetal liver cells were purified by flow cytometry into the following immunophenotypically defined populations: (A) E10.5 diploid platelet-forming cells (megakaryocytic lineage, CD45-CD144-CD41high), E10.5 haematopoietic progenitor cells (CD45+CD41low), E10.5 myeloid cells (CD45+CD41low), and E10.5 endothelium (CD45-CD144+CD41-); and, (B) E13.5 megakaryocytes (CD61-enriched CD41+CD150+CD42D+), myeloid cells (CD45+CD11B+), and blast cells (CD45+CD11B-).
2014-07-27 | E-MTAB-2625 | biostudies-arrayexpress
Project description:To identify the binding partner of LMO2 for explanation of STAT3 signal-related protein in human glioblastoma
2022-08-11 | PXD028254 | Pride
Project description:LMO2 regulates gene expression facilitating the formation of multipartite DNA-binding complexes. In B cells, LMO2 is specifically up-regulated in the Germinal Center (GC) reaction and is expressed in GC-derived non-Hodgkin’s lymphomas. LMO2 is one of the most powerful prognostic indicators in DLBCL patients. However, its function in GC B cells and DLBCL is currently unknown. In the present study we characterized the LMO2 transcriptome and interactome in DLBCL cells. LMO2 regulates genes implicated in kinetochore function, chromosome assembly and mitosis. Overexpression of LMO2 in DLBCL cell lines results in centrosome amplification. In DLBCL, the LMO2 complex contains some of the traditional partners such as LDB1, E2A, HEB, Lyl1, ETO2 and SP1, but not TAL1 or GATA proteins. Furthermore, we identified novel LMO2 interacting partners: ELK1, NFATc1 and LEF-1 proteins. Reporter assays revealed that LMO2 increases transcriptional activity of NFATc1 and decreases transcriptional activity of LEF-1 proteins. Overall, our studies identified a novel LMO2 transcriptome and interactome in DLBCL and provide a platform for future elucidation of LMO2 function in GC B-cells and DLBCL pathogenesis. RCK8 DLBCL cell lines were stably transfected with control plasmid or plasmid+LMO2
2012-07-12 | E-GEOD-34576 | biostudies-arrayexpress
Project description:LMO2 overexpressing transgenic mouse models suggest an accumulation of immature T-cell progenitors in the thymus as main pre-leukemic event. The effects of LMO2 overexpression on human T-cell development in vivo, however, are unknown. Here we report studies of a humanized mouse model transplanted with LMO2 transduced human hematopoietic stem and progenitor cells. The effects of LMO2 overexpression were confined to the T-cell lineage although initially multipotent cells were transduced. Three effects of LMO2 on human T-cell development were observed: 1) a block at the DN/ISP stage, 2) an accumulation of CD4+CD8+ double positive CD3- cells and 3) an altered CD8/CD4 ratio with enhanced peripheral T lymphocytes Single stranded cDNA was synthesized from 1000 pg total RNA using the Ovation Pico WTA System V2 Module (NuGEN Technologies Inc, Leek, The Netherlands) in combination with the Encore Biotin Module (NuGEN Technologies Inc) according to the instructions of the manufacturer. Biotin labeling and fragmentation was performed and fragmented cDNA was hybridized onto Affymetrix Gene Atlas human U219 arrays.
2016-03-26 | E-GEOD-79625 | biostudies-arrayexpress
Project description:BACKGROUND LMO2 belongs to the LIM-Only group of LIM domain protein superfamily. It is ubiquitously expressed in different types of tissues and locates either in the nucleus or in the cytoplasm depending on the tissue type. Till now the unique function of LMO2 was considered to be serving as a bridging or blocking molecule that mediates extensive protein-protein interactions. However, the exactly biological features of LMO2 interactome as well as LMO2 function spectrum remain largely unclear. MATERIAL AND METHODS In this study, yeast 2-hybrid assay was firstly performed using LMO2 as the bait and the characteristic of LMO2 protein interactome was analyzed according to the yeast 2-hybrid data and other relative biological information primarily using bioinformatic method. RESULTS Our data indicated that LMO2 favored interacting with peptides containing ß-sheet structure and having relatively unstable confirmation. Moreover, several LMO2 favored interacting domains were identified, including WD40 repeat, coiled-coil, Ankyrin repeat, Zinc finger, PDZ, and SH3, and functions of these domain-containing members were dramatically enriched in some types of cancers. CONCLUSIONS Our results revealed a LMO2 favored protein-interaction pattern in both secondary structure and domain level, and concentrated LMO2 function in kinds of cytoplasmic metabolism pathways as well as multiple types of cancers.
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Project description:The use of intracellular antibodies as templates to derive surrogate compounds is an important objective because intracellular antibodies can be employed initially for target validation in pre-clinical assays and subsequently employed in compound library screens. LMO2 is a T cell oncogenic protein activated in the majority of T cell acute leukaemias. We have used an inhibitory intracellular antibody fragment as a competitor in a small molecule library screen using competitive surface plasmon resonance (cSPR) to identify compounds that bind to LMO2. We selected four compounds that bind to LMO2 but not when the anti-LMO2 intracellular antibody fragment is bound to it. These findings further illustrate the value of intracellular antibodies in the initial stages of drug discovery campaigns and more generally antibodies, or antibody fragments, can be the starting point for chemical compound development as surrogates of the antibody combining site.
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