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Berlin Brandenburg

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  • 1
    In: Neuro-Oncology, 2018, Vol. 20(suppl6), pp.vi276-vi277
    Description: Group 3 medulloblastoma (MB) carry the worst prognosis of all MB. The transcription factors MYC and MYCN have been suggested drivers for a subset of these tumors, with MYC amplifications (17–20%) representing the most common genetic alteration in Group 3 tumors, while MYCN amplifications (4–6%) are less frequent. To improve current treatment options for these patients, it is of crucial importance to decipher differential features of MYCN - and MYC -driven MB and to establish accurate animal models for these patients. By driving MYC from the hindbrain-specific Glutamate transporter 1 ( Glt1 ) promoter using a Tet-OFF system we established a novel murine model of MYC -driven MB (GMYC), which accurately recapitulates aggressive Group 3 MB. GMYC tumors develop without any p53 mutations and with ~70% penetrance. Tumor-prone GMYC mice can further be cured by MYC -depletion through dox treatment. Comparison of transcriptional profiles between GMYC and our MYCN -driven GTML tumors revealed that both models accurately represent Group 3 MB, while showing differential expression of key features of MYC - or MYCN -driven tumors. CDKN2A was identified as one of the top upregulated genes in our GTML model as compared to our GMYC model. CDKN2A encodes two tumor suppressors, p16INK4A and p14ARF, which are key regulators of cell cycle progression and activation of p53. Similar enhancement of CDKN2A was observed in MYCN -amplified as compared to MYC -amplified Group 3/4 patients. Tumor formation following partial or complete knockout of CDKN2A significantly increased tumor penetrance in GTML as compared to GMYC animals. Similarly, CDKN2A levels significantly correlate with poor prognosis in MYCN amplified MB patients while as compared to MYC amplified patients were CDKN2A levels are low. This suggests that MYC is regulating and suppressing CDKN2A during MB formation and further advocates that pharmacological restoration of CDKN2A would be a potential future therapy for this group of high-risk MB patients.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    Language: English
    In: Oncogene, 2014, Vol.33(39), pp.4709-4721
    Description: Proteins involved in promoting cell proliferation and viability need to be timely expressed and carefully controlled for the proper development of the brain but also efficiently degraded in order to prevent cells from becoming brain cancer cells. A major pathway for targeted protein degradation in cells...
    Keywords: Medical And Health Sciences ; Clinical Medicine ; Cancer And Oncology ; Medicin Och Hälsovetenskap ; Klinisk Medicin ; Cancer Och Onkologi ; Glioma ; Medulloblastoma ; Ubiquitin-Proteasome System ; Brain Tumor Development ; E3 Ligases
    ISSN: 0950-9232
    E-ISSN: 14765594
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  • 3
    Language: English
    In: Biological Procedures Online, 2010, Vol.12(1), pp.1-17
    Description: Dynamic chromatin structure is a fundamental property of gene transcriptional regulation, and has emerged as a critical modulator of physiological processes during cellular differentiation and development. Analysis of chromatin structure using molecular biology and biochemical assays in rare somatic stem and progenitor cells is key for understanding these processes but poses a great challenge because of their reliance on millions of cells. Through the development of a miniaturized genome-scale chromatin immunoprecipitation method (miniChIP–chip), we have documented the genome-wide chromatin states of low abundant populations that comprise hematopoietic stem cells and immediate progeny residing in murine bone marrow. In this report, we describe the miniChIP methodology that can be used for increasing an understanding of the epigenetic mechanisms underlying hematopoietic stem and progenitor cell function. Application of this method will reveal the contribution of dynamic chromatin structure in regulating the function of other somatic stem cell populations, and how this process becomes perturbed in pathological conditions.
    Keywords: Miniaturized chromatin immunoprecipitation assays ; Microarray technology ; Histone modifications ; Stem and progenitor cells ; Epigenetic regulation ; Lineage commitment
    E-ISSN: 1480-9222
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  • 4
    Language: English
    In: Biological Procedures Online, May 15, 2010, Vol.12, p.9031
    Description: Dynamic chromatin structure is a fundamental property of gene transcriptional regulation, and has emerged as a critical modulator of physiological processes during cellular differentiation and development. Analysis of chromatin structure using molecular biology and biochemical assays in rare somatic stem and progenitor cells is key for understanding these processes but poses a great challenge because of their reliance on millions of cells. Through the development of a miniaturized genome-scale chromatin immunoprecipitation method (miniChIP-chip), we have documented the genome-wide chromatin states of low abundant populations that comprise hematopoietic stem cells and immediate progeny residing in murine bone marrow. In this report, we describe the miniChIP methodology that can be used for increasing an understanding of the epigenetic mechanisms underlying hematopoietic stem and progenitor cell function. Application of this method will reveal the contribution of dynamic chromatin structure in regulating the function of other somatic stem cell populations, and how this process becomes perturbed in pathological conditions. Additional file 1 Click here for file
    Keywords: Chromatin -- Physiological Aspects ; Chromatin -- Research ; Hematopoietic Stem Cells -- Genetic Aspects ; Hematopoietic Stem Cells -- Physiological Aspects ; Hematopoietic Stem Cells -- Research ; Transcription (Genetics) -- Research
    ISSN: 1480-9222
    Source: Cengage Learning, Inc.
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  • 5
    Language: English
    In: Biological Procedures Online, May 15, 2010, Vol.12, p.9031
    Description: Dynamic chromatin structure is a fundamental property of gene transcriptional regulation, and has emerged as a critical modulator of physiological processes during cellular differentiation and development. Analysis of chromatin structure using molecular biology and biochemical assays in rare somatic stem and progenitor cells is key for understanding these processes but poses a great challenge because of their reliance on millions of cells. Through the development of a miniaturized genome-scale chromatin immunoprecipitation method (miniChIP-chip), we have documented the genome-wide chromatin states of low abundant populations that comprise hematopoietic stem cells and immediate progeny residing in murine bone marrow. In this report, we describe the miniChIP methodology that can be used for increasing an understanding of the epigenetic mechanisms underlying hematopoietic stem and progenitor cell function. Application of this method will reveal the contribution of dynamic chromatin structure in regulating the function of other somatic stem cell populations, and how this process becomes perturbed in pathological conditions. Additional file 1 Click here for file
    Keywords: Chromatin -- Physiological Aspects ; Chromatin -- Research ; Hematopoietic Stem Cells -- Genetic Aspects ; Hematopoietic Stem Cells -- Physiological Aspects ; Hematopoietic Stem Cells -- Research ; Transcription (Genetics) -- Research
    ISSN: 1480-9222
    Source: Cengage Learning, Inc.
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  • 6
    Language: English
    In: Methodology and Computing in Applied Probability, 2017, Vol. 19(4), pp. 1089-1105
    Description: Graph centralities are commonly used to identify and prioritize disease genes in transcriptional regulatory networks. Studies on small networks of experimentally validated protein-protein interactions underpin the general validity of this approach and extensions of such findings have recently been proposed for networks inferred from gene expression data. However, it is largely unknown how well gene centralities are preserved between the underlying biological interactions and the networks inferred from gene expression data. Specifically, while previous studies have evaluated the performance of inference methods on synthetic gene expression, it has not been established how the choice of inference method affects individual centralities in the network. Here, we compare two gene centrality measures between reference networks and networks inferred from corresponding simulated gene expression data, using a number of commonly used network inference methods. The results indicate that the centrality of genes is only moderately conserved for all of the inference methods used. In conclusion, caution should be exercised when inspecting centralities in reverse-engineered networks and further work will be required to establish the use of such networks for prioritizing disease genes.
    Keywords: Transcriptional Regulatory Network Inference ; Simulated Gene Expression ; Graph Centrality ; Natural Sciences ; Mathematics ; Probability Theory And Statistics ; Naturvetenskap ; Matematik ; Sannolikhetsteori Och Statistik
    ISSN: 1387-5841
    E-ISSN: 15737713
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  • 7
    Language: English
    In: Cancer Research, 2014, Vol.74(19)
    Keywords: Medical And Health Sciences ; Clinical Medicine ; Cancer And Oncology ; Medicin Och Hälsovetenskap ; Klinisk Medicin ; Cancer Och Onkologi
    ISSN: 0008-5472
    E-ISSN: 15387445
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  • 8
    Language: English
    In: Cancer Research, 07/15/2016, Vol.76(14 Supplement), pp.2688-2688
    Description: Glioma is the most frequent malignant brain tumor in adults. Platelet-derived growth factor (PDGF) signaling is commonly activated in glioma. We have used a retrovirus-driven PDGFB-induced murine glioma model that causes tumors that closely resemble human gliomas of various grades. Knowing that retroviruses have a capacity to induce insertional mutagenesis, we have employed whole genome sequencing to identify potential genes that, together with PDGFB, drive glioma development.
    Keywords: Genomes ; Brain Tumors ; Insertional Mutagenesis ; Platelet-Derived Growth Factor ; Animal Models ; Genetic Screening ; Development ; Glioma ; Retroviridae ; Development & Cell Cycle;
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 9
    Language: English
    In: Cancer Research, 07/15/2016, Vol.76(14 Supplement), pp.2473-2473
    Description: Misexpression of MYC genes (MYC and MYCN) occurs commonly in medulloblastoma (MB), the most frequent malignant childhood brain tumor. We previously showed that tumors are addicted to MYCN and that MYCN stabilization is required for MB development in mice (Swartling et al, Genes & Dev, 2010; Cancer Cell, 2012). Targeted MYCN suppression completely depleted MYCN-driven MB cells in vivo. Immediate transcriptional changes from such MYCN blockade were found by RNA-Seq and showed similarities to changes that occurred after CDK2 suppression or when inhibiting BET bromodomains. CDK2 and BET inhibitors both inhibited MYC protein expression and effectively induced cell cycle arrest or apoptosis. Compared with either agent alone a sustained combination treatment over 7-10 days displayed synergy and effectively abolished tumor cell proliferation in vitro. The combined treatment further reduced tumor growth in orthotopical MB transplants and significantly prolonged survival as compared to single agent therapy. Our data suggest that dual inhibition of CDK2 and BET Bromodomains could be a novel treatment approach in suppressing medulloblastoma by targeting MYC proteins.
    Keywords: Brain Tumors ; Myc Protein ; Apoptosis ; Data Processing ; Cell Cycle ; Medulloblastoma ; Transcription ; Children ; Cyclin-Dependent Kinase 2 ; Tumor Cells ; Cancer ; Neurobiology;
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 10
    In: Neuro-Oncology, 2018, Vol. 20(suppl6), pp.vi274-vi274
    Description: Medulloblastoma (MB) is the most prevalent malignant brain tumor in children. Based on molecular genetic profiling, this disease can be classified into four major subgroups which display distinct clinical features. Group 3 MBs are associated with overexpression or amplification of the MYC oncogene and rarely show any mutations in the tumor suppressor protein p53. Patients with MYC-driven MB have a particularly high risk of recurrence and are associated with extremely poor prognosis. Thus, modeling MYC-driven MB is critical for the development and testing of potential new treatment approaches for these high-risk MBs. Here we show the first human MB model developed from human hindbrain neuroepithelial stem (NES) cells and induced pluripotent stem cell-derived NES (iPS-NES) by lentiviral overexpression of wild-type MYC. Following orthotopic transplantation into immunodeficient mice these embryonic cells generate aggressive brain tumors with high penetrance in the absence of p53 mutations. The MYC-driven tumors are comprised of poorly differentiated cells with high expression of the proliferation marker Ki-67. Tumors also express early neuronal lineage marker Tuj-1 (neuron-specific class 3 beta tubulin) and the transcription factor OTX2. All these features closely mimic those of human Group 3 MB. The establishment of these human MYC-driven MB animal models will facilitate the functional study of MB biology and testing of potential therapies.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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