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  • 1
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; tumor ; CELL ; human ; MODEL ; DISEASE ; SITES ; GENE ; GENES ; transcription ; MICE ; NF-KAPPA-B ; COMPLEX ; COMPLEXES ; DNA ; MECHANISM ; murine ; TRANSCRIPTION FACTOR ; IMPACT ; animals ; mechanisms ; BINDING ; SEQUENCE ; SEQUENCES ; TARGET ; MOUSE ; STAGE ; TRANSCRIPTION FACTORS ; PROGRESSION ; MALIGNANCIES ; PATTERNS ; PROMOTER ; AGE ; transgenic ; leukemia ; DNA methylation ; TUMOR-SUPPRESSOR GENE ; REGION ; B-CELLS ; RECRUITMENT ; STRATEGIES ; MOUSE MODEL ; TARGETS ; REPRESSION ; METHYLATION ; TRANSCRIPTIONAL REPRESSION ; REGULATOR ; MALIGNANCY ; PROGRAM ; TUMOR-SUPPRESSOR ; CLL ; MURINE MODEL ; development ; BINDING-SITE ; USA ; EPIGENETICS ; ONSET ; CPG-ISLAND METHYLATION ; BINDING-SITES ; OCCURS ; tumor suppressor ; epigenetic ; STATE ; BINDING SITE ; histone modifications ; ABERRANT METHYLATION ; 3 ; therapeutic ; THERAPEUTIC TARGET ; WELL ; STRATEGY ; INVESTIGATE ; RATIONALE ; TRANSCRIPTION-FACTOR ; FOXD3
    Abstract: Epigenetic alterations, including gain or loss of DNA methylation, are a hallmark of nearly every malignancy. Changes in DNA methylation can impact expression of cancer-related genes including apoptosis regulators and tumor suppressors. Because such epigenetic changes are reversible, they are being aggressively investigated as potential therapeutic targets. Here we use the E mu-TCL1 transgenic mouse model of chronic lymphocytic leukemia (CLL) to determine the timing and patterns of aberrant DNA methylation, and to investigate the mechanisms that lead to aberrant DNA methylation. We show that CLL cells from E mu-TCL1 mice at various stages recapitulate epigenetic alterations seen in human CLL. Aberrant methylation of promoter sequences is observed as early as 3 months of age in these animals, well before disease onset. Abnormally methylated promoter regions include binding sites for the transcription factor FOXD3. We show that loss of Foxd3 expression due to an NF-kappa B p50/p50:HDAC1 repressor complex occurs in TCL1-positive B cells before methylation. Therefore, specific transcriptional repression is an early event leading to epigenetic silencing of target genes in murine and human CLL. These results provide strong rationale for the development of strategies to target NF-kappa B components in CLL and potentially other B-cell malignancies
    Type of Publication: Journal article published
    PubMed ID: 19666576
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  • 2
    Abstract: Epigenetic or transcriptional silencing of important tumor suppressors has been described to contribute to cell survival and tumorigenesis in chronic lymphocytic leukemia (CLL). Using gene expression microarray analysis, we found that thousands of genes are repressed more than 2-fold in CLL compared to normal B cells; however therapeutic approaches to reverse this have been limited in CLL. Following treatment with the Hsp90 inhibitor 17-DMAG, a significant number of these repressed genes were significantly re-expressed. One of the genes significantly repressed in CLL and up-regulated by 17-DMAG was suppressor of cytokine signaling 3, (SOCS3). SOCS3 has been shown to be silenced in solid tumors as well as myeloid leukemia; however little is known about the regulation in CLL. We found that 17-DMAG induces expression of SOCS3 by via the activation of p38 signaling, and subsequently inhibits AKT and STAT3 phosphorylation resulting in downstream effects on cell migration and survival. We therefore suggest that SOCS3 is an important signaling protein in CLL, and Hsp90 inhibitors represent a novel approach to target transcriptional repression in B cell lymphoproliferative disorders which exhibit a substantial degree of gene repression.
    Type of Publication: Journal article published
    PubMed ID: 27107422
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  • 3
    Keywords: CLL, genetics, methylation, epigenetics, TCL1
    Abstract: Early stages in the development of chronic lymphocytic leukemia (CLL) have not been explored mainly due to the inability to study normal B-cells en route to transformation. In order to determine such early events of leukemogenesis, we have used a well established mouse model for CLL. Over-expression of human TCL1, a known CLL oncogene in murine B-cells leads to the development of mature CD19+/CD5+/IgM+ clonal leukemia with a disease phenotype similar to that seen in human CLL. Herein, we review our recent study using this TCL1-driven mouse model for CLL and corresponding human CLL samples in a cross-species epigenomics approach to address the timing and relevance of epigenetic events occurring during leukemogenesis. We demonstrated that the mouse model recapitulates the epigenetic events that have been reported for human CLL, affirming the power and validity of this mouse model to study early epigenetic events in cancer progression. Epigenetic alterations are detected as early as three months after birth, far before disease manifests at about 11 months of age. These mice undergo NFkappaB repressor complex mediated inactivation of the transcription factor Foxd3, whose targets become aberrantly methylated and silenced in mouse and human CLL. Overall, our data suggest the accumulated epigenetic alterations during CLL pathogenesis as a consequence of gene silencing through TCL1 and NFkappaB repressor complex, suggesting the relevance for NFkappaB as a therapeutic target in CLL.
    Type of Publication: Journal article published
    PubMed ID: 19901553
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