Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Effects of Beta Catenin antagonist BC2059 in AML cells

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE61275 | GEO | 2014/12/31

SECONDARY ACCESSION(S): PRJNA260636

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Targeting Nuclear β-catenin as therapy for post-myeloproliferative neoplasm secondary AML

Project description:Transformation of post-myeloproliferative neoplasms into secondary (s) AML exhibit poor clinical outcome. In addition to increased JAK-STAT and PI3K-AKT signaling, post-MPN sAML blast progenitor cells (BPCs) demonstrate increased nuclear β-catenin levels and TCF7L2 (TCF4) transcriptional activity. Knockdown of β-catenin or treatment with BC2059 that disrupts binding of β-catenin to TBL1X (TBL1) depleted nuclear β-catenin levels. This induced apoptosis of not only JAKi-sensitive but also JAKi-persister/resistant post-MPN sAML BPCs, associated with attenuation of TCF4 transcriptional targets MYC, BCL-2 and Survivin. Co-targeting of β-catenin and JAK1/2 inhibitor ruxolitinib (rux) synergistically induced lethality in post-MPN sAML BPCs and improved survival of mice engrafted with human sAML BPCs. Notably, co-treatment with BET protein degrader ARV-771 and BC2059 also synergistically induced apoptosis and improved survival of mice engrafted with JAKi-sensitive or JAKi-persister/resistant post-MPN sAML cells. These preclinical findings highlight potentially promising anti-post-MPN sAML activity of combination of β-catenin and BETP antagonists against post-MPN sAML BPCs.

2021-09-20 | GSE120639 | GEO

Homo sapiens

Project description:Effects of Beta Catenin antagonist BC2059 in AML cells

| PRJNA260636 | ENA

Gene expression patterns in response to IL-3 in human AML patient mononuclear cells

Project description:Aberrant activation of β-catenin is a common event in Acute Myeloid Leukemia (AML), and is recognized as an independent predictor of poor prognosis. Although increased β-catenin signaling in AML has been associated with AML1-ETO and PML-RARα translocation products, and activating mutations in the FLT3 receptor, it remains unclear which mechanisms activate β-catenin in AML more broadly. Here, we describe a novel link between interleukin-3 (IL-3) signaling and the regulation of β-catenin in myeloid transformation and AML. Using a murine model of HoxB8 and IL-3 cooperation we show that IL-3 modulates β-catenin protein levels, and Cre-induced deletion of β-catenin abolishes IL-3 dependent growth and colony formation. In the erythroleukemic cell line TF-1.8, we observed increased β-catenin protein levels and nuclear localization in response to IL-3, which correlated with transcriptional induction of β-catenin target genes. Furthermore, IL-3 promoted β-catenin accumulation in a subset of AML patient samples, and microarray gene expression analysis of these cells revealed induction of WNT/β-catenin and TCF4 transcriptional gene signatures in an IL-3 dependent manner. This study is the first to link β-catenin activation to IL-3 and suggests that targeting IL-3 signaling may be an effective approach for the inhibition of β-catenin activity in some patients with AML. AML patient samples (AML1-4) were cultured in the presence or absence of hIL-3 for 6 or 16h.

2014-02-13 | E-GEOD-51402 | biostudies-arrayexpress

T-cell factor 4 and β-catenin chromatin occupancies pattern zonal liver metabolism.

Project description:β-catenin signaling can be both a physiological and an oncogenic pathway in the liver. It controls compartmentalized gene expression, allowing the liver to ensure its essential metabolic function. It is activated by mutations in 20 to 40% of hepatocellular carcinomas with specific metabolic features. We decipher the molecular determinants of β-catenin-dependent zonal transcription using mice with β-catenin-activated or -inactivated hepatocytes, characterizing in vivo their chromatin occupancy by Tcf4 and β-catenin, their transcriptome and their metabolome. We find that Tcf4 DNA-bindings depend on β-catenin. Tcf4/β-catenin binds Wnt-responsive elements preferentially around β-catenin-induced genes. In contrast, genes repressed by β-catenin bind Tcf4 on Hnf4-responsive elements. β-catenin, Tcf4 and Hnf4α interact, dictating β-catenin transcription which is antagonistic to that elicited by Hnf4α. Finally, we find the drug/bile metabolism pathway to be the one most heavily targeted by β-catenin, partly through xenobiotic nuclear receptors. We conclude that β-catenin patterns the zonal liver together with Tcf4, Hnf4α and xenobiotic nuclear receptors. This network represses lipid metabolism, and exacerbates glutamine, drug and bile metabolism, mirroring hepatocellular carcinomas with β-catenin mutational activation. In vivo liver samples in 4 conditions: Betacat activated (WCE, Tcf4 chipseq, Betacat chipseq, mRNAseq with 2 replicates), Betacat null (WCE, Tcf4 chipseq, mRNAseq with 2 replicates), Betacat control (mRNAseq with 2 replicates), Wild type (mRNAseq with 2 replicates)

2014-01-18 | E-GEOD-35213 | biostudies-arrayexpress

Mechanistic basis and efficacy of targeting Beta Catenin-TCF7L2-JMJD6-MYC Axis to overcome resistance to BET inhibitors [no drug]

Project description:Promising activity of BET protein inhibitors (BETis) is compromised by adaptive or innate resistance in AML. Here, modeling of BETi- persister/resistance (BETi-P/R) in human post-MPN secondary AML (sAML) cells demonstrated accessible and active chromatin in specific super-enhancers/enhancers, which was associated with increased levels of nuclear β-catenin, TCF7L2, JMJD6, and c-Myc in BETi-P/R sAML cells. Following BETi treatment, c-Myc levels were rapidly restored in BETi-P/R sAML cells. CRISPR/Cas9-mediated knockout of TCF7L2 or JMJD6 reversed BETi-P/R, whereas ectopic overexpression conferred BETi-P/R in sAML cells; confirming the mechanistic role of the β-catenin-TCF7L2- JMJD6-MYC axis in BETi-resistance. Patient-derived, post-MPN, CD34+ sAML blasts exhibiting relative resistance to BETi, as compared to sensitive sAML blasts, displayed higher mRNA and protein expressions of TCF7L2, JMJD6 and c-Myc, and following BETi washout exhibited rapid restoration of c-Myc and JMJD6. CRISPR/Cas9 knockout of TCF7L2 and JMJD6 depleted their levels, inducing loss of viability of the sAML blasts. Disruption of co-localization of nuclear β-catenin with TBL1 and TCF7L2 by the small molecule inhibitor BC2059 combined with depletion of BRD4 by BET-PROTAC reduced c-Myc levels and exerted synergistic lethality in BETi-P/R sAML cells. This combination also reduced leukemia burden and improved survival of mice engrafted with BETi-P/R sAML cells or with patient-derived AML blasts innately resistant to BETi. Therefore, multi- targeted disruption of β-catenin-TCF7L2-JMJD6-MYC axis overcomes adaptive and innate BETi-resistance, exhibiting pre-clinical efficacy against human post-MPN sAML cells.

2020-11-06 | GSE145275 | GEO

Mechanistic basis and efficacy of targeting Beta Catenin-TCF7L2-JMJD6-MYC Axis to overcome resistance to BET inhibitors [OTX015]

2020-11-06 | GSE145274 | GEO

Mechanistic basis and efficacy of targeting Beta Catenin-TCF7L2-JMJD6-MYC Axis to overcome resistance to BET inhibitors [ChIP-seq]

2020-11-06 | GSE145023 | GEO

Gene expression patterns in response to IL-3 in human AML patient mononuclear cells

2014-02-13 | GSE51402 | GEO

T-cell factor 4 and β-catenin chromatin occupancies pattern zonal liver metabolism.

2014-01-18 | GSE35213 | GEO

Transcriptome analysis of MDA-MB-231 breast cancer cells in which VASP gene was knocked down

Project description:Previous studies have shown that the main function of VASP is to regulate the cytoskeleton and play an important role in promoting tumor cell metastasis. In this study, we first reveal that VASP is located in the nucleus of breast cancer cells and elucidate a Wnt/β-catenin/VASP positive feedback loop. We identify that VASP is a target gene of Wnt/β-catenin signaling pathway, and activation of Wnt/β-catenin signaling pathway can significantly upregulate VASP protein expression, while upregulated VASP protein can in turn promote translocation of β-catenin and DVL3 proteins into the nucleus. In the nucleus, VASP, DVL3, β-catenin and TCF4 can form VASP/DVL3/β-catenin/TCF4 protein complex, activating Wnt/β-catenin signaling pathway, and promoting the expression of target genes VASP, c-myc and cyclin D1. Thus, our study reveals that there is a Wnt/β-catenin/VASP malignant positive feedback loop in breast cancer, which promotes the proliferation and migration of breast cancer cells, and breaking this positive feedback loop may provide new strategy for breast cancer treatment.

2022-12-25 | GSE142702 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data