Beta-catenin deletion and GSK3b inhibition in B-ALL cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE245287 | GEO | 2025/08/08
REPOSITORIES: GEO
Similar Datasets
Project description:Canonical Wnt/B-catenin signaling is frequently dysregulated in myeloid leukemias and is implicated in leukemogenesis. Nuclear-localized β-catenin is indicative of active Wnt signaling and is frequently observed in acute myeloid leukemia (AML) patients; however, some patients exhibit little or no β-catenin nuclear-localization even where cytosolic B-catenin is abundant. Differential propensity for nuclear-localized β-catenin is also observed in cell lines. To investigate the factors mediating the nuclear-localization of B-catenin we carried out a nuclear/cytoplasmic proteomic analysis of the B-catenin interactome in myeloid leukemia cells. From this we identified hundreds of putative novel B-catenin-interactors. Comparison of interacting factors between Wnt-responsive cells (high nuclear B-catenin, K562/HEL) versus Wnt-unresponsive cells (low nuclear B-catenin, ML1) suggested the established interactor, LEF1, is a key factor mediating the nuclear-localization of B-catenin in myeloid leukemia. The relative levels of nuclear LEF1 and B-catenin were tightly correlated in both cell lines and in primary AML blasts. Furthermore, LEF1 knockdown inhibited B-catenin nuclear-localization and transcriptional activation in Wnt-responsive cells. Conversely, LEF1 overexpression was able to promote both nuclear-localization and B-catenin-dependent transcriptional responses in previously Wnt-unresponsive cells. This study is the first to present a B-catenin interactome in hematopoietic cells and reveals LEF1 as a critical regulator of canonical Wnt signaling in myeloid leukemia.
2019-01-11 | PXD009305 | Pride
Project description:The transcription factor SNAIL1 is a master regulator of epithelial-to-mesenchymal transition, a process entailing massive gene expression changes. To better understand SNAIL1-induced transcriptional reprogramming we performed time-resolved transcriptome analysis upon conditional SNAIL1 expression in colorectal cancer cells. Bioinformatic analyses indicated that SNAIL1 strongly affected Wnt/β-Catenin pathway activity. This correlated with upregulation of LEF1, a nuclear binding partner of β-Catenin. Several tumour entities, including aggressive mesenchymal colorectal cancers, exhibit positively correlated LEF1 and SNAIL1 expression, and elevated LEF1 levels parallel increased colorectal cancer patient mortality. Comparative gene expression profiling suggested that 35% of Snail1-induced transcriptional changes are attributable to LEF1. LEF1 stimulates Wnt/β-Catenin pathway feedback inhibitor expression, causes cell-cycle arrest in vitro, and retards xenograft tumour growth. Conversely, LEF1-deficiency and preventing the β-Catenin-LEF1 interaction impaired the ability of SNAIL1 to alter Wnt/β-catenin target gene expression and to induce cancer cell invasion. Although LEF1 did not autonomously induce epithelial-mesenchymal transition, LEF1 is a critical factor acting downstream of SNAIL1. Apparently, SNAIL1 employs LEF1 as alternative effector to redirect Wnt/β-catenin pathway activity towards anti-proliferative and pro-invasive gene expression.
2019-08-15 | GSE115716 | GEO
Project description:Bipolar disorder (BD) is a psychiatric condition characterized by depressive and manic episodes that affect 2% of the world population. The first-line long-term treatment for mood stabilization is lithium (Li). Induced pluripotent stem cell modeling of BD using hippocampal dentate gyrus-like neurons derived from Li responsive (LR) and Li non-responsive (NR) patients previously showed neuronal hyperexcitability. Li treatment reversed hyperexcitability only on LR neurons. In this study we searched for specific targets of Li resistance in NR neurons and found that the activity of Wnt/β-catenin signaling pathway was severely affected, with a significant decrease in expression of LEF1. Li targets the Wnt/β-catenin signaling pathway by inhibiting GSK-3β and releasing β-catenin that forms a nuclear complex with TCF/LEF1, activating the Wnt/β-catenin transcription program. Therefore, we propose that downregulation of LEF1 may account for Li resistance in NR neurons. Our results show that valproic acid (VPA), a drug used to treat NR patients that also acts downstream of GSK-3β, upregulated LEF1 and Wnt/β-catenin gene targets, increased transcriptional activity of complex β-catenin/TCF/LEF1 and reduced excitability in NR neurons. Additionally, decreasing LEF1 expression in control neurons using shLEF1 caused hyperexcitability, confirming that the impact of VPA on excitability in NR neurons was connected to changes in LEF1 and in the Wnt/β-catenin pathway. Our results suggest that LEF1 may be a useful target for the discovery of new drugs for BD treatment.
2022-06-01 | GSE159487 | GEO
Project description:Somatic mutations in APC or CTNNB1 genes lead to aberrant Wnt signaling and colorectal cancer (CRC) initiation and progression. Activation of Wnt pathway leads to the formation of beta-catenin-T-cell factor/Lymphoid enhancer binding factor 1 (Tcf/Lef1) complexes that activate transcription of oncogenic target genes. Lef1 is the only member of the Tcf gene family that is not expressed in the normal intestine, but is induced during intestinal tumorigenesis. Thus, we wanted to assess the role of Lef1 using genetic mouse models of intestinal adenomas and scRNA-seq technology. Tumorigenesis was initiated by inducing Apc mutation in Lgr5+ stem cells. Intestinal EpCAM+ epithelial cells of Lgr5-CreERT;Apc fl/fl (LApc) mouse and Lgr5-CreERT;Apc fl/fl; Lef1 fl/fl (LApcL) mouse were used to analyze the effects of Lef1 deletion in intestinal adenoma cells. We used WT mice as a control to distinguish adenoma cells.
2021-12-10 | GSE179483 | GEO
Project description:To determine the global transcriptomic changes induced by treatment with the Beta Catenin antagonist BC2059 in AML cells The canonical WNT-β-catenin pathway is essential for self-renewal, growth and survival of AML stem/blast progenitor cells (BPCs). Deregulated WNT signaling inhibits degradation of β-catenin, causing increased nuclear translocation and co-factor activity of β-catenin with the transcriptional regulator TCF4/LEF1 in AML BPCs. Here, we determined the pre-clinical anti-AML activity of the anthraquinone oxime-analog BC2059 (BC), known to attenuate β-catenin levels. BC treatment disrupted the binding of β-catenin with the scaffold protein TBL1 (transducin β-like 1) and proteasomal degradation and decline in the nuclear levels of β-catenin. This was associated with reduced transcriptional activity of TCF4 and expression of its target genes, cyclin D1, c-Myc and survivin. BC treatment dose-dependently induced apoptosis of cultured and primary AML BPCs. Treatment with BC also significantly improved the median survival of immune-depleted mice engrafted with either cultured or primary AML BPCs exhibiting nuclear expression of β-catenin. Co-treatment with the pan-histone deacetylase inhibitor panobinostat and BC synergistically induced apoptosis of cultured and primary AML BPCs, including those expressing FLT3-ITD, as well as further significantly improved the survival of immune-depleted mice engrafted with primary AML BPCs. These findings underscore the promising pre-clinical activity and warrant further testing of BC against human AML, especially those expressing FLT3-ITD.
2014-12-31 | GSE61275 | GEO
Project description:Lef1 is a critical transducer of the Wnt/beta-catenin signaling pathway that is essential for mesoderm differentiation in vertebrate embryos. We established a doxycycline inducible ES cell line to over-express Flag-tagged Lef1 in differentiating ES cells which have the capacity to form mesoderm cells in vitro. The goal of this study was to identify the genes/gene networks regulated by Lef1 to understand how it regulates mesoderm differentiation and to establish the Lef1-regulated, Wnt/beta-catenin transcriptome. Total RNA was extracted from ES cells after 3 days of differentiating following Lef1 over-expression from day 2 to 3. We compared the transcriptome of differentially expressed genes in untreated and doxycycline treated ES cells to identify Lef1 regulated genes.
2016-04-01 | E-GEOD-73083 | biostudies-arrayexpress
Project description:During embryonic kidney development, nephron progenitor cells (NPCs) self-renew and differentiate into all cells in mature nephrons. The Wnt signaling components Wnt9b and β-catenin are required for both NPC self-renewal and differentiation. A low level of Wnt/β-catenin are associated with NPC self-renewal while a high level with differentiation. To investigate the transcriptional mechanisms behind Wnt/β-catenin-driven regulation of NPCs states, we modeled NPC self-renewal and differentiation in vitro with NPEM (Brown et al., 2015) supplemented with low (1.25 μM) or high (5 μM) concentration of CHIR22091 (CHIR), a small molecule GSK3β inhibitor that stabilizes β-catenin. We have found the Tcf/Lef family repressors Tcf7l1 and Tcf7l2 are enriched in low CHIR condition, while the activators Tcf7 and Lef1 in high CHIR condition, correlating with the NPC differentiation program transiting from being repressed to activated. To identify direct transcriptional targets of Tcf/Lef factors and β-catenin, here we generated ChIP-Seq data from primary NPC, as well as NPC cultured in low and high CHIR concentration.
2021-01-07 | GSE131117 | GEO
Project description:AML with chromosomal alterations involving 3q26 overexpress the transcription factor (TF) EVI1, associated with therapy refractoriness and inferior overall survival in AML. Consistent with a CRISPR screen highlighting BRD4 dependency, treatment with BET inhibitor (BETi) repressed EVI1, LEF1, c-Myc, c-Myb, CDK4/6, and MCL1, and induced apoptosis of AML cells with 3q26 lesions. Tegavivint (TV, BC-2059), known to disrupt binding of nuclear β-catenin and TCF7L2/LEF1 with TBL1, also inhibited co-localization of EVI1 with TBL1 and dose-dependently induced apoptosis in AML cell lines and patient-derived (PD) AML cells with 3q26.2 lesions. TV treatment repressed EVI1, attenuated enhancer activity at ERG, TCF7L2, GATA2 and MECOM loci, abolished interactions between MYC enhancers, repressing AML stemness while upregulating mRNA gene-sets of interferon/inflammatory response, TGF-β signaling and apoptosis-regulation. Co-treatment with TV and BETi or venetoclax induced synergistic in vitro lethality and reduced AML burden, improving survival of NSG mice harboring xenografts of AML with 3q26.2 lesions.
2024-05-06 | GSE247093 | GEO
Project description:AML with chromosomal alterations involving 3q26 overexpress the transcription factor (TF) EVI1, associated with therapy refractoriness and inferior overall survival in AML. Consistent with a CRISPR screen highlighting BRD4 dependency, treatment with BET inhibitor (BETi) repressed EVI1, LEF1, c-Myc, c-Myb, CDK4/6, and MCL1, and induced apoptosis of AML cells with 3q26 lesions. Tegavivint (TV, BC-2059), known to disrupt binding of nuclear β-catenin and TCF7L2/LEF1 with TBL1, also inhibited co-localization of EVI1 with TBL1 and dose-dependently induced apoptosis in AML cell lines and patient-derived (PD) AML cells with 3q26.2 lesions. TV treatment repressed EVI1, attenuated enhancer activity at ERG, TCF7L2, GATA2 and MECOM loci, abolished interactions between MYC enhancers, repressing AML stemness while upregulating mRNA gene-sets of interferon/inflammatory response, TGF-β signaling and apoptosis-regulation. Co-treatment with TV and BETi or venetoclax induced synergistic in vitro lethality and reduced AML burden, improving survival of NSG mice harboring xenografts of AML with 3q26.2 lesions.
2024-05-06 | GSE247092 | GEO
Project description:AML with chromosomal alterations involving 3q26 overexpress the transcription factor (TF) EVI1, associated with therapy refractoriness and inferior overall survival in AML. Consistent with a CRISPR screen highlighting BRD4 dependency, treatment with BET inhibitor (BETi) repressed EVI1, LEF1, c-Myc, c-Myb, CDK4/6, and MCL1, and induced apoptosis of AML cells with 3q26 lesions. Tegavivint (TV, BC-2059), known to disrupt binding of nuclear β-catenin and TCF7L2/LEF1 with TBL1, also inhibited co-localization of EVI1 with TBL1 and dose-dependently induced apoptosis in AML cell lines and patient-derived (PD) AML cells with 3q26.2 lesions. TV treatment repressed EVI1, attenuated enhancer activity at ERG, TCF7L2, GATA2 and MECOM loci, abolished interactions between MYC enhancers, repressing AML stemness while upregulating mRNA gene-sets of interferon/inflammatory response, TGF-β signaling and apoptosis-regulation. Co-treatment with TV and BETi or venetoclax induced synergistic in vitro lethality and reduced AML burden, improving survival of NSG mice harboring xenografts of AML with 3q26.2 lesions.
2024-05-06 | GSE247091 | GEO