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Overexpression of LMO2 causes aberrant human T-cell development in vivo by three potentially distinct cellular mechanisms

ABSTRACT: 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE79625 | GEO | 2016/03/26

SECONDARY ACCESSION(S): PRJNA316470

REPOSITORIES: GEO

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Overexpression of LMO2 causes aberrant human T-cell development in vivo by three potentially distinct cellular mechanisms

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

Requirement for Lyl1 in a model of Lmo2-driven early T-cell precursor ALL

Project description:To determine the requirement for Lyl1 in Lmo2-driven T-ALL, microarray data was perepared from sorted CD4-CD8 double negative thymocytes of wild-type, Lmo2 transgenic and Lmo2-transgenic, Lyl1 knockout mice. Total RNA obtained from sorted CD4-CD8 double-negative thymocytes

2013-07-25 | E-GEOD-49164 | biostudies-arrayexpress

RNA-seq and anti-LMO2 ChIP-seq data in primary T cells in different stages from LMO2 over-expressing C57BL/6J transgenic mice

Project description:In this study, to investigate the pathogenic role of transcriptional regulator LMO2 during T lineage development, we isolated DN1, DN3, DP, CD4SP, CD8SP thymocytes, splenic CD4+ T cells and splenic CD8+ T cells from wild type and LMO2 over-expressing C57BL/6J mice for RNA-seq, and DN3 (CD25+), DP thymocytes, splenic CD4+/CD8+ T cells from transgenic mice and wild type DN3 (CD25+) thymocytes for ChIP-seq.

2023-11-01 | GSE186943 | GEO

Requirement for Lyl1 in a model of Lmo2-driven early T-cell precursor ALL

2013-07-25 | GSE49164 | GEO

Lmo2 is dispensable for maintenance of most Lmo2-induced murine T-cell leukemias

Project description:Lmo2 is an oncogenic transcription factor that is a frequent target of chromosomal abnormalities in this T-cell acute lymphoblastic leukemia (T-ALL). In transgenic mouse models, overexpression of Lmo2 causes thymocyte self-renewal leading to T-cell leukemia with long latency. However, the requirement of Lmo2 for maintenance of overt leukemia is poorly understood. We found that Lyl1, a critical cofactor for Lmo2-induced leukemia, is frequently lost in cell lines derived from Lmo2-transgenic mice, raising the possibility that Lmo2 function is dispensable at this stage. To study this, we developed a Tetracycline-repressible knock-in mouse model (Vav-TRE-Lmo2), which expresses Lmo2 throughout the haematopoietic system. This led to specific effects on T-cell development and the development of T-cell leukemia with long latency, preceded by the presence of self-renewing T-cells in the thymus. Repression of Lmo2 overcame the Lmo2-induced thymocyte developmental block at the preleukemic stage and led to elimination of Lmo2-induced thymocyte self-renewal in vivo. In contrast, Lmo2 function was dispensable for the majority of overt Lmo2-induced T-cell leukemias as well as leukemia-derived cell lines, implying an evolution of oncogene addiction in the majority of T-cell leukemias. Lmo2-dependence in T-ALL was associated with an immature gene expression profile, but could not be predicted by immunophenotype or assessment of Notch pathway activation. Thus, Lmo2 can give rise to both Lmo2-depenent and –independent T-cell leukemias. The Vav-TRE-Lmo2 model should be useful to determine the molecular features associated with Lmo2-dependence, as well as the critical components of the Lmo2-induced self-renewal pathways in T-ALL.

2022-01-01 | GSE125674 | GEO

Identification of LMO2 transcriptome and interactome in diffuse large B-cell lymphoma

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

Identification of LMO2 transcriptome and interactome in diffuse large B-cell lymphoma

2012-07-13 | GSE34576 | GEO

Human LMO2 binding protein LC-MSMS in U87MG(Glioblastoma cell)

Project description:To identify the binding partner of LMO2 for explanation of STAT3 signal-related protein in human glioblastoma

2022-08-11 | PXD028254 | Pride

Transcriptional Changes during T cell development following conditional loss of Bcl6

Project description:In this study we investigated the changes during T cell development in Rag knockout Bcl6 conditional knockout E16.5 thymi compared to Control E16.5 thymi. We measured the transcription changes by RNA seq in three different populations including CD25+, CD8+CD4- (ISP) and CD8+CD4+ (DP) thymocytes.

2020-09-24 | GSE152944 | GEO

Whole Genome Expression Array in Human T-cell Acute Lymphoblastic Leukemia

Project description:Childhood T-ALL samples were compared with thymocyte subsets we compared key molecules of wnt signaling pathway in our cohort RNA was isolated from the bone marrow samples of childhood T-ALL patients at the time of diagnosis with a blast count over 90% and hybridized to Affymetrix GeneChip HU-133 Plus.2 .Thymic subsets were sorted by FACS and labeled as DN(CD3,CD4,CD8 neg), DP3poz tot(CD3,CD4,CD8poz), DP3neg(CD3neg,CD4,CD8poz), ISP(Immature single positive), SP4(Single positive CD4), SP8 (Single positive CD8).

2013-04-19 | E-GEOD-46170 | biostudies-arrayexpress

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