RNA-seq profiling of thymocytes from wildtype and Lmo2-transgenic mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE188225 | GEO | 2023/03/09
REPOSITORIES: GEO
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Project description:RNA-seq profiling of thymocytes from wildtype and Lmo2-transgenic mice
| PRJNA777946 | ENA
Project description:Transcriptional profiling of Lmo2 transgenic DN thymocytes
2010-01-22 | E-TABM-860 | biostudies-arrayexpress
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: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:T-cell Acute Lymphoblastic Leukaemia (T-ALL) can be classified into a number of subfamilies, including those that overexpress TAL1/LMO, TLX1/3 and HOXA transcription factors. Whilst it has been previously shown in mouse models that TAL1/LMO transcription factors induce thymocyte self-renewal, whether this is the case for other transcription factor subclasses is currently unknown. To address this, we have studied vav-Nup98-HoxD13-transgenic (NHD13-Tg) mice, a model of HOXA-driven T-ALL, which overexpress HOXA transcription factors throughout haematopoiesis and display features of myelodysplastic syndrome in the bone marrow along with T-cell developmental abnormalities in the thymus and subsequent development of T-ALL in approximately 15% of mice. Thymocytes from preleukemic NHD13-Tg mice could engraft long-term in serial transplantation assays, demonstrating that NHD13-Tg thymocytes have acquired self-renewal capacity. Transcriptome analysis showed that NHD13-Tg thymocytes exhibited a Stem Cell like transcriptional program which closely resembled that of Lmo2 transgenic thymocytes, including Lmo2 itself and the critical Lmo2 cofactor Lyl1, suggesting a common mechanism of thymocyte self-renewal in these models. To determine whether Lmo2/Lyl1 are required for NHD13-induced thymocyte self-renewal, NHD13-Tg mice were crossed with Lyl1 knockout mice to generate NHD13-Tg mice lacking Lyl1. This showed that Lyl1 is essential for expression of the stem cell-like gene expression program in NHD13-Tg thymocytes and for thymocyte self-renewal. Surprisingly however, absence of Lyl1 accelerated the onset of T-ALL in NHD13-Tg mice. These studies demonstrate that Lyl1 is essential for self-renewal of NHD13-Tg thymocytes, suggesting that Lmo2 and Lyl1 may mediate thymocyte self-renewal induced by a variety of T-cell oncogenes. However, whilst Lyl1-induced thymocyte self-renewal is essential for Lmo2-driven T-cell leukemia, NHD13 can also promote T-ALL via an alternative pathway.
2019-03-04 | GSE121641 | 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: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
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.
2012-07-13 | GSE34576 | GEO
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