Rapid Tumor Formation of Human T-Cell Leukemia Virus Type 1-Infected Cell Lines in Novel NOD-SCID/γc<sup>null</sup>Mice: Suppression by an Inhibitor against NF-κB

Dewan, M. Zahidunnabi; Terashima, Kazuo; Taruishi, Midori; Hasegawa, Hideki; Ito, Mamoru; Tanaka, Yuetsu; Mori, Nozomu; Sata, Tetsutaro; Koyanagi, Yoshio; Maeda, Masako; Kubuki, Yoko; Okayama, Akira; Fujii, Masahiro; Yamamoto, Naoki

doi:10.1128/jvi.77.9.5286-5294.2003

Cited by 103 publications

(89 citation statements)

References 53 publications

(36 reference statements)

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“…SCID models of ATL have proven useful in examining treatment strategies for ATL. Variable success in tumor suppression has been achieved with the proteasome inhibitor, PS-341 (Tan and Waldmann, 2002), humanized anti-CD2 monoclonal antibody (Zhang et al, 2003b), an NF-kB inhibitor (Dewan et al, 2003), and humanized anti-CD52 monoclonal antibody (Zhang et al, 2003a). Recently, SCID mice less than 5 weeks old with low NK cell activity developed rapid tumor formation resulting in death (Ohsugi et al, 2004).…”

Section: Tumor Transplant Models In Micementioning

confidence: 99%

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Animal models for human T-lymphotropic virus type 1 (HTLV-1) infection and transformation

2005

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Over the past 25 years, animal models of human T-lymphotropic virus type 1 (HTLV-1) infection and transformation have provided critical knowledge about viral and host factors in adult T-cell leukemia/lymphoma (ATL). The virus consistently infects rabbits, some non-human primates, and to a lesser extent rats. In addition to providing fundamental concepts in viral transmission and immune responses against HTLV-1 infection, these models have provided new information about the role of viral proteins in carcinogenesis. Mice and rats, in particular immunodeficient strains, are useful models to assess immunologic parameters mediating tumor outgrowth and therapeutic invention strategies against lymphoma. Genetically altered mice including both transgenic and knockout mice offer important models to test the role of specific viral and host genes in the development of HTLV-1-associated lymphoma. Novel approaches in genetic manipulation of both HTLV-1 and animal models are available to address the complex questions that remain about viral-mediated mechanisms of cell transformation and disease. Current progress in the understanding of the molecular events of HTLV-1 infection and transformation suggests that answers to these questions are approachable using animal models of HTLV-1-associated lymphoma Oncogene (2005) 24, 6005-6015.

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Section: Tumor Transplant Models In Micementioning

confidence: 99%

“…In several of these studies, the majority of the cell death was found to be due to apoptosis. An inhibitor of NF-kB DNA-binding activity, Bay 11-7082, was also shown to block NF-kB activity and resulted in tumor regression in ATL-transplanted NOD-SCID-gammac knockout mice (Dewan et al, 2003).…”

Section: Therapeutic Modalities In Htlv-1 Animal Modelsmentioning

confidence: 99%

Animal models for human T-lymphotropic virus type 1 (HTLV-1) infection and transformation

2005

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“…ATL-35T, 81-66/45, MJ, MT-2 and ATL-102 cells are known to express Tax ('Tax-active'), whereas ED-40515(À) and TL-Om1 cells are known not to express Tax ('Tax-inactive'). 14,[21][22][23][24][25] As shown in Figure 1a, the phosphorylation of IkBa at Ser32 and p65 at Ser536 were detected in all cell lines except Jurkat, a control T-cell line, in the absence of any stimuli. We also detected prominent band of p100/p52 in five Tax-active cell lines, but not in Tax-inactive and control cell lines.…”

Section: Constitutive Nf-kb Activation In Htlv-1-infected T-cell Linementioning

confidence: 99%

Induction of cell death in adult T-cell leukemia cells by a novel IκB kinase inhibitor

et al. 2006

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NF-jB is constitutively activated in adult T-cell leukemia (ATL) and is considered responsible for cell growth and prevention of cell death. In this study, we demonstrate that NF-jB is constitutively activated in various HTLV-1-infected T-cell lines and ATL-derived cell lines irrespectively of Tax expression as evidenced by the phosphorylation of IjBa and p65 subunit of NF-jB, activation of NF-jB DNA binding, and upregulation of various target genes including bcl-x L , bcl-2, XIAP, c-IAP1, survivin, cyclinD1, ICAM-1 and VCAM-1. The effects of a novel IjB kinase (IKK) inhibitor, 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile (ACHP), were examined on cell growth of these cell lines and fresh ATL leukemic cells. We found that ACHP could inhibit the phosphorylation of IjBa and p65, as well as NF-jB DNA-binding, associated with downregulation of the NF-jB target genes and induce cell growth arrest and apoptosis in these cells. When Tax-active and Tax-inactive cell lines were compared, ACHP could preferentially inhibit cell growth of Tax-active cells. Moreover, ACHP exhibited strong apoptosis-inducing activity in fresh ATL cells. These findings indicate that ACHP and its derivatives are effective in inducing ATL cell death and thus feasible candidates for the treatment of ATL.

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“…Nuclear extracts were prepared as described previously. 15) Nuclear extracts (5 µg of protein) were incubated in 12 µl of binding buffer (10 mmol/ liter HEPES, pH 7.8, 100 mmol/liter NaCl, 1 mmol/liter EDTA, 2.5% glycerol), 1 µg of poly [d(I-C)] and 32 P-labeled κB probe derived from the H-2K promoter for 30 min at room temperature. To identify the subunits constituting the NF-κB complexes, specific Abs against p50, c-Rel (Santa Cruz Biotechnology), p65 (#1226), RelB (#13482) (from Dr. Nancy Rice), and p52 (#1319) (from Upstate Biotechnology) were used.…”

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confidence: 99%

“…This is a unique type of animal, lacking both T-and B-cells and having defects in NK activity, macrophage function, complement activity, and dendritic cell function. 15,16) MM cell lines were inoculated either subcutaneously (s.c.) in the post-auricular region or intravenously (i.v.) in the tail of NOG mice enabling both macroscopic and microscopic observation of the mechanism of tumorigenesis and malignant growth of MM.…”

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confidence: 99%

Prompt tumor formation and maintenance of constitutive NF‐κB activity of multiple myeloma cells in NOD/SCID/γC^null mice

et al. 2004

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Clinically and biologically relevant animal models are indispensable to evaluate both the pathophysiology and strategies for diagnosis and treatment of multiple myeloma (MM) ultiple myeloma (MM) is a B-cell neoplasm characterized by clonal expansion of plasma cells in the bone marrow, and is associated with neoangiogenesis and often with severe bone disease..1-4) MM has a poor prognosis and a very short survival time, mainly because of poor efficacy of conventional and transplantation therapy. To develop novel therapies and to study the pathophysiology, a good animal model of this disease is needed. Such a model would require high engraftment efficiency and conservation of relevant tumor features.Severe combined immunodeficiency (SCID) mice have been utilized in studies on the mechanism of MM and on therapeutic strategy.5-10) However, this model has five major drawbacks, i.e., that tumor formation requires a long period of time, repeated transplantation, total body irradiation, and human fetal bone and anti-gp130 mAbs. Depending on the type of treatment, immunosuppressive conditioning releases a cascade of pro-inflammatory cytokines, 11) which strongly influence the activities of various cell types of tumor stroma, such as fibroblasts, myoepithelial cells, and macrophages, that are in close functional interaction with adjacent tumor cells. [12][13][14] Therefore, such treatments could lead to changes in relevant histomorphologic or functional features of tumors implanted into respective recipients. Furthermore, immunosuppressive pretreatment, such as irradiation, alters the expression patterns of adhesion molecules in peripheral tissues.11) This may influence immune cell migration into such sites, causing difficulties in the interpretation of cellular transfer studies in such models.11) In the present study, we have used a newly developed SCID mouse strain, the NOD/SCID/γc null (NOG) mouse, in order to overcome such problems. This is a unique type of animal, lacking both T-and B-cells and having defects in NK activity, macrophage function, complement activity, and dendritic cell function.15, 16) MM cell lines were inoculated either subcutaneously (s.c.) in the post-auricular region or intravenously (i.v.) in the tail of NOG mice enabling both macroscopic and microscopic observation of the mechanism of tumorigenesis and malignant growth of MM.We show here that a progressively growing large tumor was rapidly and reproducibly induced in all mice inoculated with cells of the MM cell line within only 2 to 3 weeks, and infiltration of the tumor cells was observed in various organs of NOG mice. Tumor cells sustained a strong NF-κB activity in vivo, which might play an important role in the cell proliferation of MM. These results suggest that the NOG mouse model of MM should be useful for investigating the in vivo molecular pathogenesis, infiltration into different organs, and therapeutic measures for MM patients. Materials and MethodsMice and cell lines. NOG mice were obtained from the Central Institute for Experimenta...

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Rapid Tumor Formation of Human T-Cell Leukemia Virus Type 1-Infected Cell Lines in Novel NOD-SCID/γc^nullMice: Suppression by an Inhibitor against NF-κB

Cited by 103 publications

References 53 publications

Animal models for human T-lymphotropic virus type 1 (HTLV-1) infection and transformation

Animal models for human T-lymphotropic virus type 1 (HTLV-1) infection and transformation

Induction of cell death in adult T-cell leukemia cells by a novel IκB kinase inhibitor

Prompt tumor formation and maintenance of constitutive NF‐κB activity of multiple myeloma cells in NOD/SCID/γC^null mice

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Rapid Tumor Formation of Human T-Cell Leukemia Virus Type 1-Infected Cell Lines in Novel NOD-SCID/γcnullMice: Suppression by an Inhibitor against NF-κB

Cited by 103 publications

References 53 publications

Animal models for human T-lymphotropic virus type 1 (HTLV-1) infection and transformation

Animal models for human T-lymphotropic virus type 1 (HTLV-1) infection and transformation

Induction of cell death in adult T-cell leukemia cells by a novel IκB kinase inhibitor

Prompt tumor formation and maintenance of constitutive NF‐κB activity of multiple myeloma cells in NOD/SCID/γCnull mice

Contact Info

Product

Resources

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Rapid Tumor Formation of Human T-Cell Leukemia Virus Type 1-Infected Cell Lines in Novel NOD-SCID/γc^nullMice: Suppression by an Inhibitor against NF-κB

Prompt tumor formation and maintenance of constitutive NF‐κB activity of multiple myeloma cells in NOD/SCID/γC^null mice