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Article ; Online: DRUGPATH - a novel bioinformatic approach identifies DNA-damage pathway as a regulator of size maintenance in human ESCs and iPSCs.

Kovacic, Boris / Rosner, Margit / Schlangen, Karin / Kramer, Nina / Hengstschläger, Markus

2019 Volume 9, Issue 1, Page(s) 1897

Abstract: Genetic and biochemical screening approaches often fail to identify functionally relevant pathway networks because many signaling proteins contribute to multiple gene ontology pathways. We developed a DRUGPATH-approach to predict pathway-interactomes ... ...

Abstract	Genetic and biochemical screening approaches often fail to identify functionally relevant pathway networks because many signaling proteins contribute to multiple gene ontology pathways. We developed a DRUGPATH-approach to predict pathway-interactomes from high-content drug screen data. DRUGPATH is based upon combining z-scores of effective inhibitors with their corresponding and validated targets. We test DRUGPATH by comparing homeostatic pathways in human embryonic stem cells (hESCs), human induced pluripotent stem cells (hiPSCs) and human amniotic fluid stem cells (hAFSCs). We show that hAFSCs utilize distinct interactomes compared to hESCs/hiPSCs and that pathways orchestrating cell cycle and apoptosis are strongly interconnected, while pathways regulating survival and size are not. Interestingly, hESCs/hiPSCs regulate their size by growing exact additional sizes during each cell cycle. Chemical and genetic perturbation studies show that this "adder-model" is dependent on the DNA-damage pathway. In the future, the DRUGPATH-approach may help to predict novel pathway interactomes from high-content drug screens.
MeSH term(s)	Apoptosis/drug effects ; Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors ; Ataxia Telangiectasia Mutated Proteins/genetics ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Size/drug effects ; Computational Biology/methods ; DNA Damage ; Dimethyl Sulfoxide/pharmacology ; Enzyme Inhibitors/pharmacology ; Human Embryonic Stem Cells ; Humans ; Indazoles/pharmacology ; Induced Pluripotent Stem Cells ; RNA Interference ; RNA, Small Interfering/metabolism ; Sulfonamides/pharmacology
Chemical Substances	2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine ; Enzyme Inhibitors ; Indazoles ; RNA, Small Interfering ; Sulfonamides ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; Dimethyl Sulfoxide (YOW8V9698H)
Language	English
Publishing date	2019-02-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-37491-w
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Article ; Online: Full biological characterization of human pluripotent stem cells will open the door to translational research.

Kramer, Nina / Rosner, Margit / Kovacic, Boris / Hengstschläger, Markus

Archives of toxicology

2016 Volume 90, Issue 9, Page(s) 2173–2186

Abstract: Since the discovery of human embryonic stem cells (hESC) and human-induced pluripotent stem cells (hiPSC), great hopes were held for their therapeutic application including disease modeling, drug discovery screenings, toxicological screenings and ... ...

Abstract	Since the discovery of human embryonic stem cells (hESC) and human-induced pluripotent stem cells (hiPSC), great hopes were held for their therapeutic application including disease modeling, drug discovery screenings, toxicological screenings and regenerative therapy. hESC and hiPSC have the advantage of indefinite self-renewal, thereby generating an inexhaustible pool of cells with, e.g., specific genotype for developing putative treatments; they can differentiate into derivatives of all three germ layers enabling autologous transplantation, and via donor-selection they can express various genotypes of interest for better disease modeling. Furthermore, drug screenings and toxicological screenings in hESC and hiPSC are more pertinent to identify drugs or chemical compounds that are harmful for human, than a mouse model could predict. Despite continuing research in the wide field of therapeutic applications, further understanding of the underlying basic mechanisms of stem cell function is necessary. Here, we summarize current knowledge concerning pluripotency, self-renewal, apoptosis, motility, epithelial-to-mesenchymal transition and differentiation of pluripotent stem cells.
MeSH term(s)	Animal Testing Alternatives ; Apoptosis/drug effects ; Biological Assay ; Cell Cycle/drug effects ; Cell Differentiation ; Cell Lineage ; Cell Movement/drug effects ; Cell Self Renewal/drug effects ; Cell Transformation, Neoplastic/chemically induced ; Cells, Cultured ; Epithelial-Mesenchymal Transition/drug effects ; Humans ; Induced Pluripotent Stem Cells/drug effects ; Induced Pluripotent Stem Cells/metabolism ; Induced Pluripotent Stem Cells/pathology ; Phenotype ; Risk Assessment ; Toxicity Tests/methods ; Translational Medical Research/methods
Language	English
Publishing date	2016-06-21
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	124992-7
ISSN	1432-0738 ; 0340-5761
ISSN (online)	1432-0738
ISSN	0340-5761
DOI	10.1007/s00204-016-1763-2
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Article ; Online: eIF3 controls cell size independently of S6K1-activity.

Schipany, Katharina / Rosner, Margit / Ionce, Loredana / Hengstschläger, Markus / Kovacic, Boris

Oncotarget

2015 Volume 6, Issue 27, Page(s) 24361–24375

Abstract: All multicellular organisms require a life-long regulation of the number and the size of cells, which build up their organs. mTOR acts as a signaling nodule for the regulation of protein synthesis and growth. To activate the translational cascade, mTOR ... ...

Abstract	All multicellular organisms require a life-long regulation of the number and the size of cells, which build up their organs. mTOR acts as a signaling nodule for the regulation of protein synthesis and growth. To activate the translational cascade, mTOR phosphorylates S6 kinase (S6K1), which is liberated from the eIF3-complex and mobilized for activation of its downstream targets. How S6K1 regulates cell size remains unclear. Here, we challenged cell size control through S6K1 by specifically depleting its binding partner eIF3 in normal and transformed cell lines. We show that loss of eIF3 leads to a massive reduction of cell size and cell number accompanied with an unexpected increase in S6K1-activity. The hyperactive S6K1-signaling was rapamycin-sensitive, suggesting an upstream mTOR-regulation. A selective S6K1 inhibitor (PF-4708671) was unable to interfere with the reduced size, despite efficiently inhibiting S6K1-activity. Restoration of eIF3 expression recovered size defects, without affecting the p-S6 levels. We further show that two, yet uncharacterized, cancer-associated mutations in the eIF3-complex, have the capacity to recover from reduced size phenotype, suggesting a possible role for eIF3 in regulating cancer cell size. Collectively, our results uncover a role for eIF3-complex in maintenance of normal and neoplastic cell size - independent of S6K1-signaling.
MeSH term(s)	Cell Proliferation ; Cell Size ; Cell Transformation, Neoplastic ; Enzyme Inhibitors/chemistry ; Eukaryotic Initiation Factor-3/metabolism ; Fibroblasts/metabolism ; Gene Expression Regulation, Neoplastic ; HEK293 Cells ; Humans ; Imidazoles/chemistry ; Mutation ; Phenotype ; Phosphorylation ; Piperazines/chemistry ; RNA, Small Interfering/metabolism ; Ribosomal Protein S6 Kinases, 70-kDa/antagonists & inhibitors ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	Enzyme Inhibitors ; Eukaryotic Initiation Factor-3 ; Imidazoles ; PF-4708671 ; Piperazines ; RNA, Small Interfering ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Ribosomal Protein S6 Kinases, 70-kDa (EC 2.7.11.1) ; ribosomal protein S6 kinase, 70kD, polypeptide 1 (EC 2.7.11.1)
Language	English
Publishing date	2015-09-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.4458
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Article ; Online: Clinical impact of studying epithelial-mesenchymal plasticity in pluripotent stem cells.

Kovacic, Boris / Rosner, Margit / Schipany, Katharina / Ionce, Loredana / Hengstschläger, Markus

European journal of clinical investigation

2015 Volume 45, Issue 4, Page(s) 415–422

Abstract: Background: The ability of cells to travel long distances in order to form tissues and organs is inherently connected to embryogenesis. The process in which epithelial-like embryonic cells become motile and invasive is termed 'epithelial-to-mesenchymal ... ...

Abstract	Background: The ability of cells to travel long distances in order to form tissues and organs is inherently connected to embryogenesis. The process in which epithelial-like embryonic cells become motile and invasive is termed 'epithelial-to-mesenchymal transition' (EMT), while the reversion of this programme--yielding differentiated cells and organs--is called 'mesenchymal-to-epithelial transition' (MET). Design: Here, we review the processes of EMT and MET in development and cancer and combine them with knowledge from pluripotent stem cell research. Results: Research has shown that these processes are activated in many cancers leading to dissemination of cancer cells throughout the body and formation of metastasis. While the regulation of EMT during cancer progression has been extensively studied for decades, many fundamental processes that govern normal development are only poorly understood. Recent discoveries, such as reprogramming to pluripotent stem cells and identification of ground and primed states of pluripotent stem cells, have redirected much attention to EMT and MET. Conclusion: Findings from pluripotent stem cell research and EMT/MET should be combined in order to design future strategies aimed to improve our understanding of cancer progression and to help develop novel anticancer strategies.
MeSH term(s)	Cell Differentiation ; Embryonic Development ; Epithelial-Mesenchymal Transition/physiology ; Humans ; Neoplasms/physiopathology ; Pluripotent Stem Cells/physiology
Language	English
Publishing date	2015-04
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	186196-7
ISSN	1365-2362 ; 0014-2972 ; 0960-135X
ISSN (online)	1365-2362
ISSN	0014-2972 ; 0960-135X
DOI	10.1111/eci.12415
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Article ; Online: Engineering AvidCARs for combinatorial antigen recognition and reversible control of CAR function.

Salzer, Benjamin / Schueller, Christina M / Zajc, Charlotte U / Peters, Timo / Schoeber, Michael A / Kovacic, Boris / Buri, Michelle C / Lobner, Elisabeth / Dushek, Omer / Huppa, Johannes B / Obinger, Christian / Putz, Eva M / Holter, Wolfgang / Traxlmayr, Michael W / Lehner, Manfred

Nature communications

2020 Volume 11, Issue 1, Page(s) 4166

Abstract: T cells engineered to express chimeric antigen receptors (CAR-T cells) have shown impressive clinical efficacy in the treatment of B cell malignancies. However, the development of CAR-T cell therapies for solid tumors is hampered by the lack of truly ... ...

Abstract	T cells engineered to express chimeric antigen receptors (CAR-T cells) have shown impressive clinical efficacy in the treatment of B cell malignancies. However, the development of CAR-T cell therapies for solid tumors is hampered by the lack of truly tumor-specific antigens and poor control over T cell activity. Here we present an avidity-controlled CAR (AvidCAR) platform with inducible and logic control functions. The key is the combination of (i) an improved CAR design which enables controlled CAR dimerization and (ii) a significant reduction of antigen-binding affinities to introduce dependence on bivalent interaction, i.e. avidity. The potential and versatility of the AvidCAR platform is exemplified by designing ON-switch CARs, which can be regulated with a clinically applied drug, and AND-gate CARs specifically recognizing combinations of two antigens. Thus, we expect that AvidCARs will be a highly valuable platform for the development of controllable CAR therapies with improved tumor specificity.
MeSH term(s)	Animals ; Antigens, Neoplasm/immunology ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; Cells, Cultured ; Cytokines/immunology ; Cytokines/metabolism ; Cytotoxicity, Immunologic/immunology ; Humans ; Immunotherapy, Adoptive/methods ; Lymphocyte Activation/immunology ; Mice, Inbred NOD ; Mice, Knockout ; Mice, SCID ; Neoplasms/immunology ; Neoplasms/pathology ; Neoplasms/therapy ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/immunology ; Receptors, Antigen, T-Cell/metabolism ; Receptors, Chimeric Antigen/genetics ; Receptors, Chimeric Antigen/immunology ; Receptors, Chimeric Antigen/metabolism ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
Chemical Substances	Antigens, Neoplasm ; Cytokines ; Receptors, Antigen, T-Cell ; Receptors, Chimeric Antigen
Language	English
Publishing date	2020-08-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-020-17970-3
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Article ; Online: Lactotransferrin-Cre reporter mice trace neutrophils, monocytes/macrophages and distinct subtypes of dendritic cells.

Kovacic, Boris / Hoelbl-Kovacic, Andrea / Fischhuber, Katrin M / Leitner, Nicole R / Gotthardt, Dagmar / Casanova, Emilio / Sexl, Veronika / Müller, Mathias

Haematologica

2014 Volume 99, Issue 6, Page(s) 1006–1015

Abstract: Considerable effort has been expended to identify genes that account for myeloid lineage commitment and development. However, currently available non-invasive mouse models utilize myeloid-specific reporters that are significantly expressed in ... ...

Abstract	Considerable effort has been expended to identify genes that account for myeloid lineage commitment and development. However, currently available non-invasive mouse models utilize myeloid-specific reporters that are significantly expressed in hematopoietic stem cells as well as lymphoid compartments. Here, we describe a myeloid-specific marker that is not shared by any other lineage. We show that lactotransferrin mRNA is expressed by Gr-1(+)/CD11b(+) cells in the bone marrow, as opposed to hematopoietic stem cells or any peripheral cell population. To follow the progeny of lactotransferrin-expressing bone marrow cells, we generated a mouse model in which a reporter gene is irreversibly activated from the lactotransferrin-promoter. We found that lactotransferrin-reporter labels a majority of neutrophils, monocytes, macrophages and distinct subtypes of dendritic cells, while excluding T, B, natural killer cells, interferon-producing killer dendritic cells, plasmacytoid dendritic cells, erythrocytes and eosinophils. Lactotransferrin-reporter(-) bone marrow cells retain lymphoid, erythroid and long-term repopulating potential, while lactotransferrin-reporter(+) bone marrow cells confer only myeloid, but not lymphoid potential. We conclude that lactotransferrin represents a late stage differentiation marker of neutrophils, macrophages and distinct subtypes of dendritic cells.
MeSH term(s)	Animals ; CD11b Antigen/metabolism ; Cell Tracking ; Dendritic Cells/metabolism ; Erythroid Cells/metabolism ; Gene Expression ; Gene Order ; Genes, Reporter ; Genetic Vectors/genetics ; Lactoferrin/genetics ; Lactoferrin/metabolism ; Lymphocytes/metabolism ; Macrophages/metabolism ; Mice ; Mice, Transgenic ; Monocytes/metabolism ; Myeloid Cells/metabolism ; Neutrophils/metabolism ; Organ Specificity/genetics ; Promoter Regions, Genetic ; RNA, Messenger/genetics ; Receptors, Chemokine/metabolism
Chemical Substances	CD11b Antigen ; Gr-1 protein, mouse ; Ltf protein, mouse ; RNA, Messenger ; Receptors, Chemokine ; Lactoferrin (EC 3.4.21.-)
Language	English
Publishing date	2014-02-21
Publishing country	Italy
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2013.097154
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Article ; Online: STAT3 promotes melanoma metastasis by CEBP-induced repression of the MITF pathway.

Swoboda, Alexander / Soukup, Robert / Eckel, Oliver / Kinslechner, Katharina / Wingelhofer, Bettina / Schörghofer, David / Sternberg, Christina / Pham, Ha T T / Vallianou, Maria / Horvath, Jaqueline / Stoiber, Dagmar / Kenner, Lukas / Larue, Lionel / Poli, Valeria / Beermann, Friedrich / Yokota, Takashi / Kubicek, Stefan / Krausgruber, Thomas / Rendeiro, André F /

Bock, Christoph / Zenz, Rainer / Kovacic, Boris / Aberger, Fritz / Hengstschläger, Markus / Petzelbauer, Peter / Mikula, Mario / Moriggl, Richard

Oncogene

2020 Volume 40, Issue 6, Page(s) 1091–1105

Abstract: Metastatic melanoma is hallmarked by its ability of phenotype switching to more slowly proliferating, but highly invasive cells. Here, we tested the impact of signal transducer and activator of transcription 3 (STAT3) on melanoma progression in ... ...

Abstract	Metastatic melanoma is hallmarked by its ability of phenotype switching to more slowly proliferating, but highly invasive cells. Here, we tested the impact of signal transducer and activator of transcription 3 (STAT3) on melanoma progression in association with melanocyte inducing transcription factor (MITF) expression levels. We established a mouse melanoma model for deleting Stat3 in melanocytes with specific expression of human hyperactive NRAS
MeSH term(s)	Animals ; CCAAT-Enhancer-Binding Protein-beta/genetics ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Disease Models, Animal ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Melanocytes/drug effects ; Melanoma/genetics ; Melanoma/pathology ; Mice ; Microphthalmia-Associated Transcription Factor/genetics ; Neoplasm Metastasis ; STAT3 Transcription Factor/genetics ; Signal Transduction/drug effects
Chemical Substances	CCAAT-Enhancer-Binding Protein-beta ; Cebpb protein, mouse ; Microphthalmia-Associated Transcription Factor ; Mitf protein, mouse ; STAT3 Transcription Factor ; Stat3 protein, mouse
Language	English
Publishing date	2020-12-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/s41388-020-01584-6
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Article ; Online: Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression.

Nature immunology

2017 Volume 18, Issue 3, Page(s) 293–302

Abstract: The aggregation of hypertrophic macrophages constitutes the basis of all granulomatous diseases, such as tuberculosis or sarcoidosis, and is decisive for disease pathogenesis. However, macrophage-intrinsic pathways driving granuloma initiation and ... ...

Abstract	The aggregation of hypertrophic macrophages constitutes the basis of all granulomatous diseases, such as tuberculosis or sarcoidosis, and is decisive for disease pathogenesis. However, macrophage-intrinsic pathways driving granuloma initiation and maintenance remain elusive. We found that activation of the metabolic checkpoint kinase mTORC1 in macrophages by deletion of the gene encoding tuberous sclerosis 2 (Tsc2) was sufficient to induce hypertrophy and proliferation, resulting in excessive granuloma formation in vivo. TSC2-deficient macrophages formed mTORC1-dependent granulomatous structures in vitro and showed constitutive proliferation that was mediated by the neo-expression of cyclin-dependent kinase 4 (CDK4). Moreover, mTORC1 promoted metabolic reprogramming via CDK4 toward increased glycolysis while simultaneously inhibiting NF-κB signaling and apoptosis. Inhibition of mTORC1 induced apoptosis and completely resolved granulomas in myeloid TSC2-deficient mice. In human sarcoidosis patients, mTORC1 activation, macrophage proliferation and glycolysis were identified as hallmarks that correlated with clinical disease progression. Collectively, TSC2 maintains macrophage quiescence and prevents mTORC1-dependent granulomatous disease with clinical implications for sarcoidosis.
MeSH term(s)	Animals ; Cell Line ; Cyclin-Dependent Kinase 4/metabolism ; Disease Progression ; Granuloma/drug therapy ; Granuloma/immunology ; Humans ; Macrophages/drug effects ; Macrophages/immunology ; Mechanistic Target of Rapamycin Complex 1 ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Multiprotein Complexes/metabolism ; RNA, Small Interfering/genetics ; Sarcoidosis/drug therapy ; Sarcoidosis/immunology ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism ; Tuberous Sclerosis Complex 2 Protein ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism
Chemical Substances	Multiprotein Complexes ; RNA, Small Interfering ; TSC2 protein, human ; Tsc2 protein, mouse ; Tuberous Sclerosis Complex 2 Protein ; Tumor Suppressor Proteins ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Cyclin-Dependent Kinase 4 (EC 2.7.11.22)
Language	English
Publishing date	2017-01-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/ni.3655
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Zs.A 5294: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Stat5 regulates cellular iron uptake of erythroid cells via IRP-2 and TfR-1.

Kerenyi, Marc A / Grebien, Florian / Gehart, Helmuth / Schifrer, Manfred / Artaker, Matthias / Kovacic, Boris / Beug, Hartmut / Moriggl, Richard / Müllner, Ernst W

Blood

2008 Volume 112, Issue 9, Page(s) 3878–3888

Abstract: Erythropoiesis strictly depends on signal transduction through the erythropoietin receptor (EpoR)-Janus kinase 2 (Jak2)-signal transducer and activator of transcription 5 (Stat5) axis, regulating proliferation, differentiation, and survival. The exact ... ...

Abstract	Erythropoiesis strictly depends on signal transduction through the erythropoietin receptor (EpoR)-Janus kinase 2 (Jak2)-signal transducer and activator of transcription 5 (Stat5) axis, regulating proliferation, differentiation, and survival. The exact role of the transcription factor Stat5 in erythropoiesis remained puzzling, however, since the first Stat5-deficient mice carried a hypomorphic Stat5 allele, impeding full phenotypical analysis. Using mice completely lacking Stat5--displaying early lethality--we demonstrate that these animals suffer from microcytic anemia due to reduced expression of the antiapoptotic proteins Bcl-x(L) and Mcl-1 followed by enhanced apoptosis. Moreover, transferrin receptor-1 (TfR-1) cell surface levels on erythroid cells were decreased more than 2-fold on erythroid cells of Stat5(-/-) animals. This reduction could be attributed to reduced transcription of TfR-1 mRNA and iron regulatory protein 2 (IRP-2), the major translational regulator of TfR-1 mRNA stability in erythroid cells. Both genes were demonstrated to be direct transcriptional targets of Stat5. This establishes an unexpected mechanistic link between EpoR/Jak/Stat signaling and iron metabolism, processes absolutely essential for erythropoiesis and life.
MeSH term(s)	Anemia, Iron-Deficiency/genetics ; Anemia, Iron-Deficiency/metabolism ; Anemia, Iron-Deficiency/pathology ; Animals ; Apoptosis ; Biological Transport, Active ; Embryo Loss ; Erythroid Cells/metabolism ; Erythroid Cells/pathology ; Female ; Iron/deficiency ; Iron/metabolism ; Iron Regulatory Protein 2/metabolism ; Liver/embryology ; Liver/metabolism ; Liver/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myeloid Cell Leukemia Sequence 1 Protein ; Pregnancy ; Proto-Oncogene Proteins c-bcl-2/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Receptors, Transferrin/metabolism ; STAT5 Transcription Factor/deficiency ; STAT5 Transcription Factor/genetics ; STAT5 Transcription Factor/metabolism
Chemical Substances	Mcl1 protein, mouse ; Myeloid Cell Leukemia Sequence 1 Protein ; Proto-Oncogene Proteins c-bcl-2 ; RNA, Messenger ; Receptors, Transferrin ; STAT5 Transcription Factor ; Tfrc protein, mouse ; Iron (E1UOL152H7) ; Iron Regulatory Protein 2 (EC 4.2.1.3)
Language	English
Publishing date	2008-08-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2008-02-138339
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Article ; Online: Authentication of primordial characteristics of the CLBL-1 cell line prove the integrity of a canine B-cell lymphoma in a murine in vivo model.

Rütgen, Barbara C / Willenbrock, Saskia / Reimann-Berg, Nicola / Walter, Ingrid / Fuchs-Baumgartinger, Andrea / Wagner, Siegfried / Kovacic, Boris / Essler, Sabine E / Schwendenwein, Ilse / Nolte, Ingo / Saalmüller, Armin / Murua Escobar, Hugo

PloS one

2012 Volume 7, Issue 6, Page(s) e40078

Abstract: Cell lines are key tools in cancer research allowing the generation of neoplasias in animal models resembling the initial tumours able to mimic the original neoplasias closely in vivo. Canine lymphoma is the major hematopoietic malignancy in dogs and ... ...

Abstract	Cell lines are key tools in cancer research allowing the generation of neoplasias in animal models resembling the initial tumours able to mimic the original neoplasias closely in vivo. Canine lymphoma is the major hematopoietic malignancy in dogs and considered as a valuable spontaneous large animal model for human Non-Hodgkin's Lymphoma (NHL). Herein we describe the establishment and characterisation of an in vivo model using the canine B-cell lymphoma cell line CLBL-1 analysing the stability of the induced tumours and the ability to resemble the original material. CLBL-1 was injected into Rag2(-/-)γ(c) (-/-) mice. The generated tumor material was analysed by immunophenotyping and histopathology and used to establish the cell line CLBL-1M. Both cell lines were karyotyped for detection of chromosomal aberrations. Additionally, CLBL-1 was stimulated with IL-2 and DSP30 as described for primary canine B-cell lymphomas and NHL to examine the stimulatory effect on cell proliferation. CLBL-1 in vivo application resulted in lymphoma-like disease and tumor formation. Immunophenotypic analysis of tumorous material showed expression of CD45(+), MHCII(+), CD11a(+) and CD79αcy(+). PARR analysis showed positivity for IgH indicating a monoclonal character. These cytogenetic, molecular, immunophenotypical and histological characterisations of the in vivo model reveal that the induced tumours and thereof generated cell line resemble closely the original material. After DSP30 and IL-2 stimulation, CLBL-1 showed to respond in the same way as primary material. The herein described CLBL-1 in vivo model provides a highly stable tool for B-cell lymphoma research in veterinary and human medicine allowing various further in vivo studies.
MeSH term(s)	Animals ; Cell Line, Tumor ; Disease Models, Animal ; Dogs ; Immunophenotyping ; Lymphoma, B-Cell/pathology ; Mice ; Mice, Knockout ; Real-Time Polymerase Chain Reaction
Language	English
Publishing date	2012-06-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0040078
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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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Order via subito