Expression data from CD19-positive splenic B cells isolated from 1-month old ID4+/-TCL1-tg and ID4+/+TCL1-tg mice
Ontology highlight
ABSTRACT: The function of ID4 in CLL development was studied in vivo using TCL1 transgenic mouse model that develop leukemia similar to human CLL. TCL1 mice with ID4 single knockout gene have accelerated CLL progression. Results from the animal study suggest ID4 as a tumor suppressor gene that might regulate cell proliferation and apoptosis in B lymphocytes. Gene expression in CD19-positive splenic B cells collected from 1-month old ID4+/-TCL1-tg and ID4+/+TCL1-tg mice was compared by microarray, the goal is to find ID4-regulated genes involved in CLL development.
Project description:Tcl1 tg mice develop a chronic lymphocytic leukemia (CLL) -like disease. To investigate the contribution of the adhesion molecule CD44 to CLL pathophysiology, we developed a CD19Cre CD44flox/flox Tcl1 tg mouse with a B cell specific CD44 deficiency (CD44ΔB Tcl1 tg). We used the Clariom S mouse microarray from Affymetrix to investigate transcriptional differeneces between Tcl1 tg and CD44ΔB Tcl1 tg mice
Project description:The function of ID4 in CLL development was studied in vivo using TCL1 transgenic mouse model that develop leukemia similar to human CLL. TCL1 mice with ID4 single knockout gene have accelerated CLL progression. Results from the animal study suggest ID4 as a tumor suppressor gene that might regulate cell proliferation and apoptosis in B lymphocytes.
Project description:TCL1 is an an oncogene and transgenic (Tg) mice expressing TCL1 specifically in B-cells are well-characterized models for chronic lymphocytic leukemia. On the contrary, PTPROt is a phosphatase with tumor suppressor characteristics in many cancers including leukemia. Our hypothesis was that transgenic expression of PTPROt in the B-cells of TCL1 Tg mice will alleviate disease phenotype and allow the study of the in vivo mechanism of action of PTPROt. To test this we have generated Tg mice with B-cell specific expression of PTPROt and crossed these mice with the TCL1 Tg mice.
Project description:POU transcription factor Pou5f1 (Oct3/4) is required to maintain ES cells in an undifferentiated state. Here we show that global expression profiling of Oct3/4-manipulated ES cells delineates the downstream target genes of Oct3/4. Combined with data from genome-wide chromatin-immunoprecipitation assays, this analysis identifies not only primary downstream targets of Oct3/4, but also secondary or tertiary targets. Furthermore, the analysis also reveals that downstream target genes are regulated either positively or negatively by Oct3/4. Identification of a group of genes that show both activation and repression depending on Oct3/4 expression levels provides a possible mechanism for the requirement of appropriate Oct3/4 expression to maintain undifferentiated ES cells. As a proof-of-principle study, one of the downstream genes, Tcl1, has been analyzed in detail. We show that Oct3/4 binds to the promoter region of Tcl1 and activates its transcription. We also show that Tcl1 is involved in the regulation of proliferation, but not differentiation, in ES cells. These findings suggest that the global expression profiling of gene-manipulated ES cells can help to delineate the structure and dynamics of gene regulatory networks.
Project description:Transcriptome analysis of RNA samples from leukemia cells of ROR1xTCL1 and TCL1 transgenic mice Animals engrafted with ROR1xTCL1 leukemia-cells developed more aggressive disease than mice engrafted with TCL1 leukemia cells. Transcriptome analysis of RNA samples from leukemia ROR1xTCL1 transgenic mice revealed shared common gene expression signatures that were distinct from those of TCL1 leukemia-cells. We performed microarray transcriptome analyses on isolated leukemia cells that developed in ROR1xTCL1 Tg mice (n=4) or TCL1 Tg mice (n=4) using the Affymetrix Mouse Exon 1.0 ST platform. Array data was processed by Affymetrix Exon Array Computational Tool. No techinical replicates were performed.
Project description:Cerebral Amyloid Angiopathy (CAA) is a significant comorbidity in almost all cases of Alzheimer’s disease (AD) and is unaddressed by current treatment regimens. We explored the Tg-SwDI mouse model which expresses human Amyloid Precursor Protein with the familial Swedish AD mutation as well as the vasculotropic Dutch and Iowa mutations leading to a phenotype of cognitive deficits with severe CAA. This is the first mapping of cerebral parenchymal proteomes of this model. In a cohort of presymptomatic mice both the cortex and hippocampus proteomes were mapped in male as well as female mice. In the four proteomes profound adaptations were identified, and previous findings of an early and severe pathology in Tg-SwDI female mice are reaffirmed on the molecular level. In addition, the effectiveness of two Carbonic Anhydrase Inhibitors (CAIs), Acetazolamide and Methazolamide, in preventing the observed molecular adaptations was evaluated. These repurposed drugs broadly prevented the proteome adaptations in the Tg-SwDI mice.
Project description:Aberrant CXCR4 activity has been implicated in lymphoma pathogenesis, disease progression and resistance to therapies. Using a mouse model with a gain-of-function CXCR4 mutation (CXCR4C1013G) that hyperactivates CXCR4 signaling, we identified CXCR4 as a crucial activator of multiple key oncogenic pathways. CXCR4 hyperactivation furthermore resulted in an expansion of transitional B1 lymphocytes, which represent the precursors of chronic lymphocytic leukemia (CLL). Indeed, CXCR4 hyperactivation led to a significant acceleration of disease onset and a more aggressive phenotype in the murine Eµ-TCL1 CLL model. Hyperactivated CXCR4 signaling cooperated with TCL1 to cause a distinct oncogenic transcriptional program in B cells, characterized by PLK1/FOXM1-associated pathways. In accordance, Eµ-TCL1;CXCR4C1013G B cells enriched a transcriptional signature from patients with Richter’s syndrome, an aggressive transformation of CLL. In summary, we here identify CXCR4 hyperactivation as a co-driver of an aggressive lymphoma phenotype. Here we make available the transcriptomic data of CD19+ B cells from bone marrow and spleen of 6-week-old WT, CXCR4C1013G, Eµ-TCL1 and Eµ-TCL1;CXCR4C1013G mice.
Project description:To assess the contribution of p66Shc deficiency to the pathogenesis of CLL we introduced a p66Shc null allele into the Emu-TCL1 mouse model of human CLL. The impact of homozygous p66Shc deletion on the pattern of gene expression in leukemic cells from the two mouse strains was compared by DNA microarray, highlighting gene candidates that were subsequently validated and assessed functionally in vitro and in vivo.