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ACGH analysis was performed in the spleen of βcat(ex3)osb mice

ABSTRACT: Cells of the osteoblast lineage affect homing, number of long term repopulating hematopoietic stem cells (HSCs) HSC mobilization and lineage determination and Blymphopoiesis . More recently osteoblasts were implicated in pre-leukemic conditions in mice. Yet, it has not been shown that a single genetic event taking place in osteoblastscan induce leukemogenesis. We show here that in mice, an activating mutation of β-catenin leading to development of acute myeloid leukemia (AML) with common chromosomal aberrationsand cell autonomous progression. Activated β-catenin stimulates expression of the Notch ligand Jagged-1 in osteoblasts. Subsequent activation of Notch signaling in HSCprogenitors induces the malignant changes. Demonstrating the pathogenetic role of theNotch pathway, genetic or pharmacological inhibition of Notch signaling ameliorates AML. Nuclear accumulation and increased β-catenin signaling in osteoblasts was also identified in 38% ofpatients with MDS/AML. These patients showed increased Notch signaling in hematopoietic cells. These findings demonstrate that genetic alterations in osteoblasts can induce AML, identify molecular signals leading to this transformation and suggest a potential novel pharmacotherapeuticapproach to AML. The present entry describes a comparison of copy numbers of DNA from βcat(ex3)osb mice from the mouse spleen with that of WT (C57BL/J Mice) mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE51690 | GEO | 2014/01/21

SECONDARY ACCESSION(S): PRJNA224570

REPOSITORIES: GEO

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aCGH analysis was performed in the spleen of Î²cat(ex3)osb mice

Project description:Cells of the osteoblast lineage affect homing, number of long term repopulating hematopoietic stem cells (HSCs) HSC mobilization and lineage determination and Blymphopoiesis . More recently osteoblasts were implicated in pre-leukemic conditions in mice. Yet, it has not been shown that a single genetic event taking place in osteoblastscan induce leukemogenesis. We show here that in mice, an activating mutation of Î²-catenin leading to development of acute myeloid leukemia (AML) with common chromosomal aberrationsand cell autonomous progression. Activated Î²-catenin stimulates expression of the Notch ligand Jagged-1 in osteoblasts. Subsequent activation of Notch signaling in HSCprogenitors induces the malignant changes. Demonstrating the pathogenetic role of theNotch pathway, genetic or pharmacological inhibition of Notch signaling ameliorates AML. Nuclear accumulation and increased Î²-catenin signaling in osteoblasts was also identified in 38% ofpatients with MDS/AML. These patients showed increased Notch signaling in hematopoietic cells. These findings demonstrate that genetic alterations in osteoblasts can induce AML, identify molecular signals leading to this transformation and suggest a potential novel pharmacotherapeuticapproach to AML. The present entry describes a comparison of copy numbers of DNA from Î²cat(ex3)osb mice from the mouse spleen with that of WT (C57BL/J Mice) mice. DNA from spleen myeloid cells from Î²cat(ex3)osb mice and WT mice were hybridized to Agilent CGH 244A arrays. DNA from spleen myeloid cells from Î²cat(ex3)osb mice in C57BL/J background was labeled with red dye. DNA from spleen myeloid cells from WT (C57BL/J) mice were labeled with green dye. There were five arrays with DNA from 1 mouse of each genotype per array.

2014-01-21 | E-GEOD-51690 | biostudies-arrayexpress

Analysis of EMCN+ bone marrow cells in Stab2-iCreF3tg/wt Ctnnb1(Ex3)fl/wt mice

Project description:Endothelial-derived Wnt/Ctnnb1-signaling is an important angiocrine regulator. Ctnnb1 gain-of-function (GOF) in sinusoidal endothelial cells was generated via Stab2-iCreF3tg/wt Ctnnb1(Ex3)fl/wt mice to analyze the effects of endothelial β-catenin signaling on bone marrow function. We used microarrays to detail the global programme of gene expression in bone marrow EMCN+ cells with β-catenin (Ctnnb1) gain-of-function compared to Wildtype.

2021-10-13 | GSE180477 | GEO

Next Generation Sequencing of β-cat lox(ex3) (Ctrl) mouse and β-cat lox(ex3);Nex-Cre (β-cat overexpression, β-cat Ovp) mouse Transcriptomes

Project description:Using RNA-seq to sequence the transcriptomes of β-cat lox(ex3) (Ctrl) and β-cat lox(ex3);Nex-Cre (β-cat Ovp) mice, we did not find significant change in the expression level of classical Wnt target genes.

2017-09-02 | GSE95629 | GEO

Expression data from epidermis of epithelial activated beta-catenin mutant mouse embryo

Project description:β-catenin signaling is required for hair follicle development, but it is unknown whether it is sufficient to activate expression of hair follicle genes in embryonic skin. To address this we profiled gene expression in epidermis from E15.5 KRT14-Cre Ctnnb1(Ex3)fl/+ embryos carrying an activating mutation in epithelial beta-catenin, and control littermate embryos. Keywords: Genetic modification

2008-05-20 | GSE10728 | GEO

Expression data from dermis of epithelial activated beta-catenin mutant mouse embryo

Project description:β-catenin signaling is required for hair follicle development, but it is unknown whether it is sufficient to activate expression of hair follicle genes in embryonic skin. To address this we profiled gene expression in dermis from E15.5 KRT14-Cre Ctnnb1(Ex3)fl/+ embryos carrying an activating mutation in epithelial beta-catenin, and control littermate embryos. Keywords: Genetic modification

2008-05-20 | GSE10727 | GEO

Expression data from skin of epithelial activated beta-catenin mutant mouse embryo

Project description:β-catenin signaling is required for hair follicle development, but it is unknown whether it is sufficient to activate expression of hair follicle genes in embryonic skin. To address this we profiled gene expression in skin dissected from E14.5 KRT14-Cre Ctnnb1(Ex3)fl/+ embryos carrying an activating mutation in epithelial beta-catenin, and control littermate embryos. Keywords: Genetic modification

2008-05-20 | GSE10726 | GEO

Notch signaling suppresses the progression of colorectal tumorigenesis

Project description:The Notch signaling pathway regulates fate decision, proliferation and differentiation of intestinal epithelial cells. However, the role of Notch signaling in colorectal cancer progression is largely unknown. Here we show that Notch signaling suppresses the progression of colorectal tumorigenesis, even though it augments tumor initiation. In contrast to adenomas of Apcmin mice, Notch-inactivated Apcmin adenomas showed more malignant characteristics, such as submucosal invasion and loss of glandular pattern. Conversely, Notch-activated Apcmin adenomas showed a reversion from high-grade to low-grade features, such as the restoration of adherent junctions. Expression profiling revealed that Notch signaling promotes the differentiation of tumor cells with down regulation of Wnt/beta-catenin target genes and inhibition of epithelial-mesenchymal transition. Comparison of mouse and human expression profiles also suggests the common role of Notch in inhibition of tumor progression. Interestingly, Notch signaling suppressed the expression of beta-catenin responsive genes through chromatin modification of Tcf4/beta-catenin binding sides. Our results suggest that Notch signaling has dual roles in colorectal tumorigenesis: promoting adenoma initiation, while inhibiting tumor progression to colorectal cancer. mRNAs from normal (WT, Notch-activated and Notch-inactivated) and tumor (WT, Notch-activated and Notch-inactivated) tissues were profiled.

2011-04-19 | E-GEOD-21392 | biostudies-arrayexpress

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

RNA-seq of SOX2 positive pituitary cells with and without activation of beta-catenin

Project description:RNA-sequencing of FACS sorted YFP +ve (I.e. SOX2 positive) cells from Sox2CreERT/+;R26YFP/+ (n=3) mice (control), and Sox2CreERT/+;CTNNB1lox(ex3)/+;R26YFP/+ (n=3) mice (with activation of beta-catenin).

2018-02-01 | E-MTAB-5538 | biostudies-arrayexpress

Analysis of liver sinusoidal endothelial cells (LSECs) with β-catenin (Ctnnb1) activation

Project description:Endothelial-derived Wnt/Ctnnb1-signaling is an important angiocrine regulator. Ctnnb1 gain-of-function (GOF) in liver sinusoidal endothelial cells was generated by crossing Clec4g-iCre (Wohlfeil SA et al, 2019, Cancer Research) with Ctnnb1(Ex3) fl/fl mice (Harada N et al, 1999, EMBO J) to analyze the effects of endothelial β-catenin signaling on LSEC differentiation and liver function We used microarrays to detail the global programme of gene expression in liver sinusoidal endothelial cells with β-catenin (Ctnnb1) gain-of-function compared to control animals.

2021-11-18 | GSE175777 | GEO

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