JMJD1B target gene screening :JMJD1B is the H3K9 demethylase involved in transcriptional activation of Lmo2 in leukemia
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE30294 | GEO | 2011/06/30
SECONDARY ACCESSION(S): PRJNA143791
REPOSITORIES: GEO
Similar Datasets
Project description:A genome-wide analysis identified a subset of JMJD1B target genes including leukemic oncogene lmo2 Total RNA obtained from isolated JMJD1B knock down stable cell in K562 cells compared to sh-CTL control stable cells.
2011-06-30 | E-GEOD-30294 | biostudies-arrayexpress
Project description:Histone lysine methylation and demethylation are considered critical steps in transcriptional regulation. In this report, we performed chromatin immunoprecipitation with microarray technology (ChIP-chip) analysis to examine the genome-wide occupancy of H3K9-me2 during all-trans-retinoic acid (ATRA)-induced differentiation of HL-60 promyelocytic leukemia cells. Using this approach, we found that KDM3B, which contains a JmjC domain, was downregulated during differentiation through the recruitment of a corepressor complex. Furthermore, KDM3B displayed histone H3K9-me1/2 demethylase activity and induced leukemogenic oncogene lmo2 expression via a synergistic interaction with CBP. Here, we found that KDM3B repressed leukemia cell differentiation and was upregulated in blood cells from acute lymphoblastic leukemia (ALL)-type leukemia patients. The combined results of this study provide evidence that the H3K9-me1/2 demethylase KDM3B might play a role in leukemogenesis via activation of lmo2 through interdependent actions with the histone acetyltransferase (HAT) complex containing CBP.
| S-EPMC3416203 | biostudies-literature
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
Project description:Prolonged or enhanced expression of the proto-oncogene Lmo2 is associated with a severe form of T-cell Acute Lymphoblastic Leukemia (T-ALL), designated Early T-progenitor ALL (ETP-ALL), that is characterized by the aberrant self-renewal and subsequent oncogenic transformation of immature thymocytes. Recent data suggest that Lmo2 may exert these effects by functioning as component of a multi-subunit transcription complex that includes the ubiquitous adapter Ldb1 along with b-HLH and/or GATA family transcription factors. In this study, we investigated the importance of Ldb1 for Lmo2-induced T-ALL by conditional deletion of Ldb1 in thymocytes in a Lmo2 transgenic mouse model of T-ALL. Our results identify a critical requirement for Ldb1 in the induction of thymocyte self-renewal, thymocyte radio-resistance and transition to T-ALL in Lmo2 transgenic mice. Ldb1 was also required for acquisition of the pre-leukemic ETP gene expression signature in immature Lmo2 transgenic thymocytes. Together, these results support a model where Lmo2-induced T-ALL results from failure to down-regulate Ldb/Lmo2 nucleated transcription complexes that normally function to enforce self-renewal in bone marrow hematopoietic progenitors
2020-03-19 | GSE129244 | GEO
Project description:We used microarrays to investigate gene expression changes in tumor-bearing Sca1-TOMATO-Lmo2 Nu/Nu mice Tumor-bearing bone marrows of three Sca1-TOMATO-Lmo2 Nu/Nu mice compared with bone marrow cells from four Control Nude mice and with thymus leukemic cells from ten Sca1-TOMATO-Lmo2 mice. GSM2209767 - GSM2209776 are re-analyses of GSE83570 (GSM2209749 - GSM220975 and GSM2209757 - GSM2209759).
2016-06-22 | E-GEOD-83571 | 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
2016-03-26 | GSE79625 | GEO
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 is an oncogenic transcription factor that is frequently overexpressed due to chromosomal abnormalities in T-cell acute lymphoblastic leukemia (T-ALL). In transgenic mouse models, Lmo2 overexpression causes thymocyte self-renewal resulting in T-cell leukemia with long latency. However, the requirement for Lmo2 for leukemia maintenance is poorly understood. To study this, we developed a Tetracycline-regulated knock-in mouse model that reversibly expresses Lmo2 throughout the haematopoietic system. This led to a specific impairment of T-cell development and the development of self-renewing preleukemic stem cells (pre-LSCs) in the thymus, followed by the development of fully penetrant T-lymphoblastic leukemia resembling human T-ALL. In preleukemic mice, repression of Lmo2 overcame the LMO2-induced thymocyte developmental block, reversed Lmo2-induced gene expression changes and eliminated self-renewing pre-LSCs in vivo. In contrast, overt T-lymphoblastic leukemias arising in this model were either immature, Lmo2-dependent leukemias resembling human ETP-ALL, or mature leukemias which were Lmo2-independent. Genomic analyses identified frequent loss of tumour suppressor genes in Lmo2-independent T-ALLs. Deletion of one of these, Ikaros (Ikzf1), was sufficient to transform Lmo2-dependent tumours to Lmo2-independence. Together these results indicate an evolution of oncogene addiction in T-ALL and that loss of Ikaros can promote self-renewal of T-ALL lymphoblasts in the absence of initiating oncogenes.
2020-12-31 | GSE144035 | GEO
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:Somatic mutations within non-coding genomic regions that aberrantly activate oncogenes have remained poorly characterized. Here we describe recurrent activating intronic mutations of LMO2, a prominent oncogene in T-cell acute lymphoblastic leukaemia (T-ALL). Heterozygous mutations were identified in PF-382 and DU.528 T-ALL cell lines, in addition to 3.7% (6/160) of paediatric and 5.5% (9/163) of adult T-ALL patient samples. The majority of indels harbor de novo MYB, ETS1 or RUNX1 consensus binding sites. Analysis of 5’-capped RNA transcripts in mutant cell lines identified the usage of an intermediate promoter site, with consequential monoallelic LMO2 overexpression. CRISPR/Cas9-mediated disruption of the mutant allele in PF-382 cells markedly downregulated LMO2 expression, establishing clear causality between the mutation and oncogene dysregulation. Furthermore, the spectrum of CRISPR/Cas9-derived mutations provide important insights into the interconnected contributions of functional transcription factor binding. Finally, these mutations occur in the same intron as retroviral integration sites in gene therapy induced T-ALL, suggesting that such events occur at preferential sites in the non-coding genome.
2017-03-15 | GSE94000 | GEO