Ldb1 is required for Lmo2 oncogene-induced thymocyte self-renewal and T-cell Acute Lymphoblastic Leukemia
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PROVIDER: PRJNA530581 | ENA |
REPOSITORIES: ENA
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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: Not available
| S-EPMC7316212 | biostudies-literature
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: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 is a component of multisubunit DNA-binding transcription factor complexes that regulate gene expression in hematopoietic stem and progenitor cell development. Enforced expression of LMO2 causes leukemia by inducing hematopoietic stem cell-like features in T-cell progenitor cells, but the biochemical mechanisms of LMO2 function have not been fully elucidated. In this study we systematically dissected the LMO2/LDB1 binding interface to investigate the role of this interaction in T-cell leukemia. Alanine scanning mutagenesis of the LIM interaction domain of LDB1 revealed a discrete motif R320LITR required for LMO2 binding. Most strikingly, co-expression of full length, wild type LDB1 increased LMO2 steady state abundance, whereas co-expression of mutant proteins deficient in LMO2 binding compromised LMO2 stability. These mutant LDB1 proteins also exerted dominant negative effects on growth and transcription in diverse leukemic cell lines. Raw gene expression data on HSB-2 cells is presented here.
2015-12-15 | GSE75839 | GEO
Project description:LMO2 is a component of multisubunit DNA-binding transcription factor complexes that regulate gene expression in hematopoietic stem and progenitor cell development. Enforced expression of LMO2 causes leukemia by inducing hematopoietic stem cell-like features in T-cell progenitor cells, but the biochemical mechanisms of LMO2 function have not been fully elucidated. In this study we systematically dissected the LMO2/LDB1 binding interface to investigate the role of this interaction in T-cell leukemia. Alanine scanning mutagenesis of the LIM interaction domain of LDB1 revealed a discrete motif R320LITR required for LMO2 binding. Most strikingly, co-expression of full length, wild type LDB1 increased LMO2 steady state abundance, whereas co-expression of mutant proteins deficient in LMO2 binding compromised LMO2 stability. These mutant LDB1 proteins also exerted dominant negative effects on growth and transcription in diverse leukemic cell lines. Raw gene expression data on HSB-2 cells is presented here. RNAseq were performed on HSB cell lines to examine their expression patterns
2015-12-15 | E-GEOD-75839 | 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:The oncoprotein NUP98-HOXD13 (NHD13) induces thymocyte self-renewal via Lmo2/Lyl1
| PRJNA497916 | ENA
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
Project description:Many questions remain about how close association of genes and distant enhancers occurs and how this is linked to transcription activation. In erythroid cells, LDB1 is recruited to the β-globin locus via LMO2 and is required for looping of the β-globin locus control region (LCR) to the active β-globin promoter. We show that the LDB1 dimerization domain (DD) is necessary and, when fused to LMO2 is sufficient, to completely restore LCR-promoter looping and transcription in LDB1 depleted cells. The looping function of the DD is unique and irreplaceable by heterologous dimerization domains. Dissection of the DD revealed distinct functional properties of conserved subdomains. Notably, a conserved helical region (DD4/5) is dispensable for LDB1 dimerization and chromatin looping but essential for transcriptional activation. DD4/5 is required for the recruitment of the co-regulators FOG1 and NuRD complex. Lack of DD4/5 alters histone acetylation and RNA polymerase II recruitment and results in failure of the locus to migrate to the nuclear interior as normally occurs during erythroid maturation. These results uncouple enhancer-promoter looping from nuclear migration and transcription activation and reveal new roles for LDB1in these processes. RNA-seq in LDB1 knockdown, LDB1 delta4/5 construct, LDB1 full-length construct, and control in induced MEL cells; three replicates each.
2014-07-02 | E-GEOD-54549 | biostudies-arrayexpress