17 results on '"Kamihira, S."'
Search Results
2. Clinical course of human T-lymphotropic virus type I carriers with molecularly detectable monoclonal proliferation of T lymphocytes: defining a low- and high-risk population
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Ikeda, S, primary, Momita, S, additional, Kinoshita, K, additional, Kamihira, S, additional, Moriuchi, Y, additional, Tsukasaki, K, additional, Ito, M, additional, Kanda, T, additional, Moriuchi, R, additional, and Nakamura, T, additional
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- 1993
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3. Semiquantitative analysis of integrated genomes of human T-lymphotropic virus type I in asymptomatic virus carriers
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Shinzato, O, primary, Ikeda, S, additional, Momita, S, additional, Nagata, Y, additional, Kamihira, S, additional, Nakayama, E, additional, and Shiku, H, additional
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- 1991
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4. Preleukemic state of adult T cell leukemia: abnormal T lymphocytosis induced by human adult T cell leukemia-lymphoma virus
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Kinoshita, K, Amagasaki, T, Ikeda, S, Suzuyama, J, Toriya, K, Nishino, K, Tagawa, M, Ichimaru, M, Kamihira, S, and Yamada, Y
- Abstract
We report the clinical, hematologic, and immunologic features of 18 preleukemic adult T cell leukemia (pre-ATL) cases with abnormal T lymphocytosis induced by human adult T cell leukemia-lymphoma virus (HTLV/ATLV). The patients were from the Nagasaki district, which is one of the most endemic areas of ATL in Japan. Pre-ATL is a subclinical T cell abnormality differing from ATL. It is characterized by an insidious onset and appearance of abnormal T lymphocytes (10% to 40%) in the peripheral blood without clinical symptoms except for a few cases transiently presenting fever, skin eruptions, and slight lymphadenopathies. Most abnormal T lymphocytes were small and mature with incised or lobulated nuclei and formed E rosettes with sheep RBCs. Virologic and biomolecular analysis revealed that all cases were infected with HTLV, and proviral DNA was integrated in host lymphocytes from 12 of the 14 cases examined. Furthermore, the lymphocyte populations, including abnormal T lymphocytes, were monoclonal with respect to the site of the provirus integration. Abnormal T lymphocytosis persisted from one to more than seven years in six cases, three of which developed ATL after a one- to five-year pre-ATL stage, whereas abnormal T lymphocytes spontaneously decreased in the other seven patients. However, HTLV-infected monoclonal lymphocytes were detected in four cases examined, even after most of the abnormal T lymphocytes had disappeared. Moreover, the same clonally provirus- integrated lymphocytes persisted in two of four cases not only during the course of abnormal lymphocytosis, but also in the subsequent almost- normal blood. These results indicate that the majority of the cases were in a pre-ATL state with a potential to develop ATL.
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- 1985
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5. Changes of adult T cell leukemia cell surface antigens at relapse or at exacerbation phase after chemotherapy defined by use of monoclonal antibodies
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Yamada, Y, Kamihira, S, Amagasaki, T, Kinoshita, K, Kusano, M, Ikeda, S, Toriya, K, Suzuyama, J, and Ichimaru, M
- Abstract
Surface phenotypes of leukemic cells from six patients with adult T cell leukemia (ATL) were analyzed by the use of monoclonal antibodies, both at the time of initial diagnosis and at either relapse or exacerbation phase after chemotherapy. Changes of cell surface antigens were observed in four of the six cases. The majority of the leukemic cells of these patients were reactive with anti-Leu-1 and anti-Leu-3a, but unreactive with anti-Leu-2a and MAS 036c monoclonal antibodies at the time of initial diagnosis, indicating that ATL cells are of peripheral inducer/helper T cell origin. In three cases, the Leu-1 antigen disappeared at relapse or at exacerbation phase, and in one of these cases, a small percentage of ATL cells became reactive with MAS 036c, which identifies cortical thymocyte antigen. ATL cells of one other case did not have Leu-1 antigen from the start, but gained Leu-2a antigen at exacerbation phase and became double-labeled cells (Leu-2a+, 3a+), which is known to be a feature of thymocytes. Thus, it appeared that ATL cells sometimes change their surface phenotype to that of an earlier stage of T cell differentiation at relapse or at exacerbation phase. Chronic myelocytic leukemia (CML) cells also usually change to immature cells at blastic crisis involving morphological change. However, this morphological change was not so prominent in the ATL cases studied, except one, in which typical ATL cells with nuclear indentation changed to large immature cells with basophilic cytoplasm at relapse.
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- 1984
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6. The transcription factor Spi-B regulates human plasmacytoid dendritic cell survival through direct induction of the antiapoptotic gene BCL2-A1.
- Author
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Karrich JJ, Balzarolo M, Schmidlin H, Libouban M, Nagasawa M, Gentek R, Kamihira S, Maeda T, Amsen D, Wolkers MC, and Blom B
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- Cell Survival physiology, Cells, Cultured, Child, Preschool, DNA-Binding Proteins genetics, Dendritic Cells cytology, Female, Hematopoietic Stem Cells cytology, Humans, Infant, Male, Minor Histocompatibility Antigens, Plasma Cells cytology, Proto-Oncogene Proteins c-bcl-2 genetics, Transcription Factors genetics, Cell Differentiation physiology, DNA-Binding Proteins metabolism, Dendritic Cells metabolism, Hematopoietic Stem Cells metabolism, Plasma Cells metabolism, Proto-Oncogene Proteins c-bcl-2 metabolism, Transcription Factors metabolism
- Abstract
Plasmacytoid dendritic cells (pDCs) selectively express Toll-like receptor (TLR)-7 and TLR-9, which allow them to rapidly secrete massive amounts of type I interferons after sensing nucleic acids derived from viruses or bacteria. It is not completely understood how development and function of pDCs are controlled at the transcriptional level. One of the main factors driving pDC development is the ETS factor Spi-B, but little is known about its target genes. Here we demonstrate that Spi-B is crucial for the differentiation of hematopoietic progenitor cells into pDCs by controlling survival of pDCs and its progenitors. In search for Spi-B target genes, we identified the antiapoptotic gene Bcl2-A1 as a specific and direct target gene, thereby consolidating the critical role of Spi-B in cell survival.
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- 2012
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7. Bortezomib suppresses function and survival of plasmacytoid dendritic cells by targeting intracellular trafficking of Toll-like receptors and endoplasmic reticulum homeostasis.
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Hirai M, Kadowaki N, Kitawaki T, Fujita H, Takaori-Kondo A, Fukui R, Miyake K, Maeda T, Kamihira S, Miyachi Y, and Uchiyama T
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- Apoptosis drug effects, Bortezomib, Cell Separation, Cytokines biosynthesis, DNA-Binding Proteins drug effects, DNA-Binding Proteins metabolism, Dendritic Cells immunology, Dendritic Cells metabolism, Endoplasmic Reticulum metabolism, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Humans, Microscopy, Confocal, Protein Transport drug effects, Regulatory Factor X Transcription Factors, Reverse Transcriptase Polymerase Chain Reaction, Toll-Like Receptors metabolism, Transcription Factors drug effects, Transcription Factors metabolism, X-Box Binding Protein 1, Boronic Acids pharmacology, Dendritic Cells drug effects, Endoplasmic Reticulum drug effects, Homeostasis drug effects, Protease Inhibitors pharmacology, Pyrazines pharmacology, Toll-Like Receptors drug effects
- Abstract
Dendritic cells (DCs) play a pivotal role in the pathogenesis of inflammatory disorders, so suppressing the activity of DCs is instrumental in treating such diseases. In the present study, we show that a proteasome inhibitor, bortezomib, suppresses the survival and immunostimulatory function of human plasmacytoid DCs (pDCs) by targeting 2 critical points, intracellular trafficking of nucleic acid-sensingToll-like receptors (TLRs) and endoplasmic reticulum (ER) homeostasis. Among the immune cells in blood, pDCs were the most susceptible to the killing effect of bortezomib. This correlates with a decrease in the spliced form of a transcription factor XBP1, which rescues cells from apoptosis by maintaining ER homeostasis. Bortezomib suppressed the production of interferon-α and interleukin-6 by pDCs activated with a TLR9-stimulating CpG DNA and a TLR7-stimulating influenza virus, which appears to be partially independent of apoptosis. Bortezomib inhibited translocation of TLR9 from the ER to endolysosomes but not of an ER membrane protein, Unc93B1, that delivers TLR9 to endolysosomes. Thus, bortezomib suppresses the activity of pDCs by inhibiting intracellular trafficking of TLRs through disrupting the coordinated translocation of TLRs and Unc93B1 and by disturbing ER homeostasis. This study suggests that proteasome inhibitors may alleviate inflammatory disorders such as lupus and psoriasis that involve pDCs.
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- 2011
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8. Human T-cell leukemia virus type I (HTLV-1) proviral load and disease progression in asymptomatic HTLV-1 carriers: a nationwide prospective study in Japan.
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Iwanaga M, Watanabe T, Utsunomiya A, Okayama A, Uchimaru K, Koh KR, Ogata M, Kikuchi H, Sagara Y, Uozumi K, Mochizuki M, Tsukasaki K, Saburi Y, Yamamura M, Tanaka J, Moriuchi Y, Hino S, Kamihira S, and Yamaguchi K
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- Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers analysis, Blotting, Southern, Carrier State, Child, DNA, Viral genetics, Disease Progression, Female, Follow-Up Studies, HTLV-I Infections blood, HTLV-I Infections epidemiology, Human T-lymphotropic virus 1 isolation & purification, Humans, Japan epidemiology, Male, Middle Aged, Prognosis, Prospective Studies, Young Adult, HTLV-I Infections virology, Human T-lymphotropic virus 1 genetics, Leukemia-Lymphoma, Adult T-Cell epidemiology, Leukemia-Lymphoma, Adult T-Cell virology, Proviruses genetics, Viral Load genetics
- Abstract
Definitive risk factors for the development of adult T-cell leukemia (ATL) among asymptomatic human T-cell leukemia virus type I (HTLV-1) carriers remain unclear. Recently, HTLV-1 proviral loads have been evaluated as important predictors of ATL, but a few small prospective studies have been conducted. We prospectively evaluated 1218 asymptomatic HTLV-1 carriers (426 males and 792 females) who were enrolled during 2002 to 2008. The proviral load at enrollment was significantly higher in males than females (median, 2.10 vs 1.39 copies/100 peripheral blood mononuclear cells [PBMCs]; P < .001), in those 40 to 49 and 50 to 59 years of age than that of those 40 years of age and younger (P = .02 and .007, respectively), and in those with a family history of ATL than those without the history (median, 2.32 vs 1.33 copies/100 PBMCs; P = .005). During follow-up, 14 participants progressed to overt ATL. Their baseline proviral load was high (range, 4.17-28.58 copies/100 PBMCs). None developed ATL among those with a baseline proviral load lower than approximately 4 copies. Multivariate Cox analyses indicated that not only a higher proviral load, advanced age, family history of ATL, and first opportunity for HTLV-1 testing during treatment for other diseases were independent risk factors for progression of ATL.
- Published
- 2010
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9. Long-term study of indolent adult T-cell leukemia-lymphoma.
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Takasaki Y, Iwanaga M, Imaizumi Y, Tawara M, Joh T, Kohno T, Yamada Y, Kamihira S, Ikeda S, Miyazaki Y, Tomonaga M, and Tsukasaki K
- Subjects
- Female, Follow-Up Studies, Humans, Japan epidemiology, Kaplan-Meier Estimate, Leukemia-Lymphoma, Adult T-Cell blood, Leukemia-Lymphoma, Adult T-Cell drug therapy, Leukemia-Lymphoma, Adult T-Cell pathology, Male, Middle Aged, Prognosis, Proportional Hazards Models, Leukemia-Lymphoma, Adult T-Cell mortality
- Abstract
The long-term prognosis of indolent adult T-cell leukemia-lymphoma (ATL) is not clearly elucidated. From 1974 to 2003, newly diagnosed indolent ATL in 90 patients (65 chronic type and 25 smoldering type) was analyzed. The median survival time was 4.1 years; 12 patients remained alive for more than 10 years, 44 progressed to acute ATL, and 63 patients died. The estimated 5-, 10-, and 15-year survival rates were 47.2%, 25.4%, and 14.1%, respectively, with no plateau in the survival curve. Although most patients were treated with watchful waiting, 12 patients were treated with chemotherapy. Kaplan-Meier analyses showed that advanced performance status (PS), neutrophilia, high concentration of lactate dehydrogenase, more than 3 extranodal lesions, more than 4 total involved lesions, and receiving chemotherapy were unfavorable prognostic factors for survival. Multivariate Cox analysis showed that advanced PS was a borderline significant independent factor in poor survival (hazard ratio, 2.1, 95% confidence interval, 1.0-4.6; P = .06), but it was not a factor when analysis was limited to patients who had not received chemotherapy. The prognosis of indolent ATL in this study was poorer than expected. These findings suggest that even patients with indolent ATL should be carefully observed in clinical practice. Further studies are required to develop treatments for indolent ATL.
- Published
- 2010
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10. Relationship between monoclonal gammopathy of undetermined significance and radiation exposure in Nagasaki atomic bomb survivors.
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Iwanaga M, Tagawa M, Tsukasaki K, Matsuo T, Yokota K, Miyazaki Y, Fukushima T, Hata T, Imaizumi Y, Imanishi D, Taguchi J, Momita S, Kamihira S, and Tomonaga M
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- Adolescent, Adult, Age Distribution, Aged, Aged, 80 and over, Child, Female, Humans, Japan epidemiology, Male, Middle Aged, Paraproteinemias etiology, Prevalence, Radiation Dosage, Radiation Injuries complications, Risk Factors, Young Adult, Nuclear Weapons, Paraproteinemias epidemiology, Radiation Injuries epidemiology, Survivors statistics & numerical data
- Abstract
Radiation exposure is a possible predisposing factor for monoclonal gammopathy of undetermined significance (MGUS), but the association has been uncertain. We investigated the relationship between radiation exposure and MGUS prevalence by using data from the M-protein screening for Nagasaki atomic bomb survivors between 1988 and 2004. Radiation exposure was assessed by exposure distance from the hypocenter and exposure radiation dose. We computed prevalence ratios (PRs) and the 95% confidence intervals (CIs) adjusting for exposure age and sex. A total of 1082 cases of MGUS were identified from 52 525 participants. MGUS prevalence was significantly higher in people exposed at distance within 1.5 km than beyond 3.0 km (PR, 1.4; 95% CI, 1.1-1.9) among those exposed at age 20 years or younger, but it was not found among those exposed at age 20 years or older. MGUS prevalence was also significantly higher in people exposed to more than 0.1 Gy than those exposed to less than 0.01 Gy (PR, 1.7; 95% CI, 1.0-2.8) among those exposed at age 20 years or younger. Thus, people exposed at younger age exhibited a significantly high risk of MGUS when exposed to a high radiation dose. There was no clear association between radiation exposure and the malignant progression of MGUS. Further detailed analysis is needed.
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- 2009
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11. A novel natural compound, a cycloanthranilylproline derivative (Fuligocandin B), sensitizes leukemia cells to apoptosis induced by tumor necrosis factor related apoptosis-inducing ligand (TRAIL) through 15-deoxy-Delta 12, 14 prostaglandin J2 production.
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Hasegawa H, Yamada Y, Komiyama K, Hayashi M, Ishibashi M, Sunazuka T, Izuhara T, Sugahara K, Tsuruda K, Masuda M, Takasu N, Tsukasaki K, Tomonaga M, and Kamihira S
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- Cell Line, Transformed, Cyclooxygenase 2 metabolism, Drug Resistance, Neoplasm drug effects, Drug Screening Assays, Antitumor, Drug Synergism, Enzyme Activation drug effects, Gene Expression Regulation, Leukemic drug effects, HL-60 Cells, Humans, Inhibitor of Apoptosis Proteins antagonists & inhibitors, Inhibitor of Apoptosis Proteins metabolism, K562 Cells, Leukemia metabolism, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins metabolism, PPAR gamma biosynthesis, Proline agonists, Proline pharmacology, Proline therapeutic use, Prostaglandin D2 metabolism, TNF-Related Apoptosis-Inducing Ligand agonists, TNF-Related Apoptosis-Inducing Ligand metabolism, TNF-Related Apoptosis-Inducing Ligand therapeutic use, Apoptosis drug effects, Leukemia drug therapy, Proline analogs & derivatives, Prostaglandin D2 analogs & derivatives, TNF-Related Apoptosis-Inducing Ligand pharmacology
- Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis in many transformed cells; however, not all human tumors respond to TRAIL, potentially limiting its therapeutic utility. Although there is substantial evidence that cytotoxic drugs can augment sensitivity to TRAIL, it has become important to know what kinds of nontoxic drugs can be used together with TRAIL. We thus screened several natural compounds that can overcome resistance to TRAIL and found that a cycloanthranilylproline derivative, Fuligocandin B (FCB), an extract of myxomycete Fuligo candida, exhibited significant synergism with TRAIL. Treatment of the TRAIL-resistant cell line KOB with FCB and TRAIL resulted in apparent apoptosis, which was not induced by either agent alone. FCB increased the production of 15-deoxy-Delta(12,14) prostaglandin J(2) (15d-PGJ(2)), an endogenous PPAR gamma ligand, through activation of cyclooxygenase-2 (COX-2). This unique mechanism highlighted the fact that 15d-PGJ(2) directly enhanced sensitivity to TRAIL by inhibiting multiple antiapoptotic factors. More importantly, similar effects were observed in other leukemia cell lines irrespective of their origin. The enhancement was observed regardless of PPAR gamma expression and was not blocked even by peroxisome proliferator-activated receptor-gamma (PPAR gamma) siRNA. These results indicate that 15d-PGJ(2) sensitizes TRAIL-resistant cells to TRAIL in a PPAR gamma-independent manner and that the use of 15d-PGJ(2) or its inducers, such as FCB, is a new strategy for cancer therapy.
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- 2007
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12. Dihydroflavonol BB-1, an extract of natural plant Blumea balsamifera, abrogates TRAIL resistance in leukemia cells.
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Hasegawa H, Yamada Y, Komiyama K, Hayashi M, Ishibashi M, Yoshida T, Sakai T, Koyano T, Kam TS, Murata K, Sugahara K, Tsuruda K, Akamatsu N, Tsukasaki K, Masuda M, Takasu N, and Kamihira S
- Subjects
- Drug Synergism, Drug Therapy, Combination, Flavonols isolation & purification, Humans, Leukemia-Lymphoma, Adult T-Cell, Plant Extracts therapeutic use, Promoter Regions, Genetic genetics, RNA, Small Interfering pharmacology, Receptors, TNF-Related Apoptosis-Inducing Ligand, Receptors, Tumor Necrosis Factor antagonists & inhibitors, Receptors, Tumor Necrosis Factor genetics, Receptors, Tumor Necrosis Factor metabolism, Signal Transduction drug effects, TNF-Related Apoptosis-Inducing Ligand, Tumor Cells, Cultured, Tumor Suppressor Protein p53 metabolism, Antineoplastic Agents therapeutic use, Apoptosis drug effects, Apoptosis Regulatory Proteins therapeutic use, Asteraceae chemistry, Drug Resistance, Neoplasm, Flavonols therapeutic use, Leukemia drug therapy, Membrane Glycoproteins therapeutic use, Tumor Necrosis Factor-alpha therapeutic use
- Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis in many transformed cells but not in normal cells and, hence, has emerged as a novel anticancer agent. Previously, we showed that although most adult T-cell leukemia/lymphoma (ATLL) cells express the TRAIL death receptor DR4 (TRAIL-R1) or DR5 (TRAIL-R2), they are resistant to TRAIL. Thus, in this study, we tried to find natural products that can overcome TRAIL resistance. Among more than 150 materials screened, a dihydroflavonol that was extracted from Blumea balsamifera (BB-1) exhibited the most striking synergism with TRAIL. Treatment of the TRAIL-resistant ATLL cell line KOB, with a combination of BB-1 and TRAIL, resulted in apparent apoptosis that was not observed on treatment with either agent alone. Furthermore, pretreatment with BB-1 followed by TRAIL further augmented the synergism. BB-1 increased the level of TRAIL-R2 promoter activity and surface protein expression in a p53-independent manner. TRAIL-R2 siRNA inhibited the synergism, indicating that sensitization was caused by the increase of TRAIL-R2 expression. More interestingly, similar effects were observed in other leukemia cell lines by exactly the same mechanisms. These results suggest that combined treatment with BB-1 and TRAIL may be a new strategy for cancer therapy.
- Published
- 2006
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13. Dual targeting of transformed and untransformed HTLV-1-infected T cells by DHMEQ, a potent and selective inhibitor of NF-kappaB, as a strategy for chemoprevention and therapy of adult T-cell leukemia.
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Watanabe M, Ohsugi T, Shoda M, Ishida T, Aizawa S, Maruyama-Nagai M, Utsunomiya A, Koga S, Yamada Y, Kamihira S, Okayama A, Kikuchi H, Uozumi K, Yamaguchi K, Higashihara M, Umezawa K, Watanabe T, and Horie R
- Subjects
- Animals, Apoptosis, Caspases metabolism, Cell Cycle, Cell Line, Cell Line, Transformed, Cell Line, Tumor, Cell Proliferation, Dose-Response Relationship, Drug, Down-Regulation, Genes, Reporter, Humans, Immunoblotting, Immunohistochemistry, Jurkat Cells, K562 Cells, Leukemia, T-Cell virology, Leukemia-Lymphoma, Adult T-Cell virology, Leukocytes, Mononuclear cytology, Leukocytes, Mononuclear metabolism, Male, Mice, Mice, SCID, Microscopy, Fluorescence, Molecular Weight, NF-kappa B metabolism, Proviruses, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Tumor Suppressor Protein p53 metabolism, Antineoplastic Agents pharmacology, Benzamides pharmacology, Cyclohexanones pharmacology, Gene Expression Regulation, Neoplastic, Human T-lymphotropic virus 1 metabolism, Leukemia, T-Cell drug therapy, Leukemia, T-Cell prevention & control, Leukemia-Lymphoma, Adult T-Cell drug therapy, NF-kappa B antagonists & inhibitors, T-Lymphocytes virology
- Abstract
Human T-cell leukemia virus type I (HTLV-1) causes adult T-cell leukemia (ATL), a fatal T-cell leukemia resistant to chemotherapy, after more than 50 years of clinical latency from transmission through breast-feeding. Polyclonal expansion of virus-infected T cells predisposes them to transformation. Constitutive activation of nuclear factor-kappaB (NF-kappaB) in the leukemic cells is essential for their growth and survival. Blocking NF-kappaB has been shown to be a potential strategy to treat ATL. We tested this approach using a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), and also examined its application to chemoprevention by selective purging of the HTLV-1-infected cells. DHMEQ inhibited NF-kappaB activation in primary ATL cells and cell lines derived from them and induced apoptotic cell death. NF-kappaB inhibition down-regulated expression of genes involved in antiapoptosis or cell-cycle progression. DHMEQ protected severe combined immunodeficiency (SCID) mice inoculated with HTLV-1-transformed cells from death. In addition, DHMEQ selectively targeted HTLV-1-infected cells in the peripheral blood of virus carriers in vitro, resulting in a decreased number of infected cells. We conclude that NF-kappaB is a potential molecular target for treatment and prevention of ATL. As a potent NF-kappaB inhibitor, DHMEQ is a promising compound allowing the translation of this strategy into clinical medicine.
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- 2005
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14. Frequent expression of CCR4 in adult T-cell leukemia and human T-cell leukemia virus type 1-transformed T cells.
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Yoshie O, Fujisawa R, Nakayama T, Harasawa H, Tago H, Izawa D, Hieshima K, Tatsumi Y, Matsushima K, Hasegawa H, Kanamaru A, Kamihira S, and Yamada Y
- Subjects
- Adult, Aged, Aged, 80 and over, Cell Line, Transformed, Chemokines, CC metabolism, Chemokines, CC pharmacology, Chemotaxis, Leukocyte drug effects, Female, Gene Products, tax pharmacology, Human T-lymphotropic virus 1, Humans, Jurkat Cells, Leukemia-Lymphoma, Adult T-Cell pathology, Male, Middle Aged, RNA, Messenger drug effects, Receptors, CCR4, Receptors, Chemokine genetics, Receptors, Chemokine physiology, Skin metabolism, Skin pathology, T-Lymphocytes metabolism, T-Lymphocytes physiology, T-Lymphocytes virology, Leukemia-Lymphoma, Adult T-Cell metabolism, Receptors, Chemokine metabolism
- Abstract
Chemokines and chemokine receptors play important roles in migration and tissue localization of various lymphocyte subsets. Here, we report the highly frequent expression of CCR4 in adult T-cell leukemia (ATL) and human T-cell leukemia virus type 1 (HTLV-1)-immortalized T cells. Flow cytometric analysis revealed that ATL and HTLV-1-immortalized T-cell lines consistently expressed CCR4. Inducible expression of HTLV-1 transcriptional activator tax in a human T-cell line Jurkat did not, however, up-regulate CCR4 mRNA. In vitro immortalization of peripheral blood T cells led to preferential outgrowth of CD4(+) T cells expressing CCR4. We further demonstrated highly frequent expression of CCR4 in fresh ATL cells by (1) reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of CCR4 expression in peripheral blood mononuclear cells (PBMCs) from patients with ATL and healthy controls; (2) flow cytometric analysis of CCR4-expressing cells in PBMCs from patients with ATL and healthy controls; (3) CCR4 staining of routine blood smears from patients with ATL; and (4) an efficient migration of fresh ATL cells to the CCR4 ligands, TARC/CCL17 and MDC/CCL22, in chemotaxis assays. Furthermore, we detected strong signals for CCR4, TARC, and MDC in ATL skin lesions by RT-PCR. Collectively, most ATL cases have apparently derived from CD4(+) T cells expressing CCR4. It is now known that circulating CCR4(+) T cells are mostly polarized to Th2 and also contain essentially all skin-seeking memory T cells. Thus, HTLV-1-infected CCR4(+) T cells may have growth advantages by deviating host immune responses to Th2. CCR4 expression may also account for frequent infiltration of ATL into tissues such as skin and lymph nodes.
- Published
- 2002
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15. Human T-cell leukemia virus type I Tax transactivates the matrix metalloproteinase-9 gene: potential role in mediating adult T-cell leukemia invasiveness.
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Mori N, Sato H, Hayashibara T, Senba M, Hayashi T, Yamada Y, Kamihira S, Ikeda S, Yamasaki Y, Morikawa S, Tomonaga M, Geleziunas R, and Yamamoto N
- Subjects
- Enzyme Induction drug effects, Humans, Leukemia-Lymphoma, Adult T-Cell enzymology, Leukemia-Lymphoma, Adult T-Cell virology, Leukemic Infiltration etiology, Matrix Metalloproteinase 9 blood, Matrix Metalloproteinase 9 physiology, NF-kappa B metabolism, Podophyllin metabolism, Podophyllotoxin analogs & derivatives, Promoter Regions, Genetic drug effects, RNA, Messenger metabolism, Tumor Cells, Cultured, Gene Products, tax pharmacology, Leukemia-Lymphoma, Adult T-Cell pathology, Leukemic Infiltration chemically induced, Matrix Metalloproteinase 9 genetics, Podophyllin analogs & derivatives, Transcriptional Activation drug effects
- Abstract
Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL) and of tropical spastic paraparesis/HTLV-I-associated myelopathy. Infiltration of various tissues by circulating leukemic cells is a characteristic of ATL. Matrix metalloproteinases (MMPs), which mediate the degradation of the basement membrane and extracellular matrix, play an important role in metastasis and tumor cell dissemination. The aim of this study was to explore whether expression of MMP-2 and MMP-9 was deregulated by HTLV-I infection. The data showed that HTLV-I-infected T-cell lines expressed high levels of MMP-9 compared with uninfected T-cell lines. In contrast, the levels of the related MMP-2 were not significantly altered by HTLV-I infection. In addition, the elevated expression of MMP-9 in HTLV-I-infected cells was attributable to the action of the viral transactivator protein Tax. The results show that Tax can activate the MMP-9 promoter and induce MMP-9 expression in T cells, indicating that the constitutive expression of MMP-9 in virus-infected cell lines is at least in part mediated by Tax. Activation of the MMP-9 promoter by Tax occurs mainly through the action of NF-kappaB and SP-1. The biologic significance of these observations was validated by the following 2 findings: MMP-9 expression was increased in primary ATL cells, and plasma MMP-9 levels were elevated in ATL patients. In addition, plasma levels of MMP-9 correlated with organ involvement in ATL patients. Together these data suggest that overexpression of MMP-9 in HTLV-I- infected cells may be in part responsible for the invasiveness of ATL cells.
- Published
- 2002
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16. Interleukin-15 (IL-15) can replace the IL-2 signal in IL-2-dependent adult T-cell leukemia (ATL) cell lines: expression of IL-15 receptor alpha on ATL cells.
- Author
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Yamada Y, Sugawara K, Hata T, Tsuruta K, Moriuchi R, Maeda T, Atogami S, Murata K, Fujimoto K, Kohno T, Tsukasaki K, Tomonaga M, Hirakata Y, and Kamihira S
- Subjects
- Adult, Antibodies metabolism, Cell Division, Dose-Response Relationship, Drug, Humans, RNA, Messenger metabolism, Receptors, Interleukin-15, Signal Transduction, Tumor Cells, Cultured, Interleukin-15 metabolism, Interleukin-2 metabolism, Leukemia, T-Cell metabolism, Receptors, Interleukin-2 biosynthesis
- Abstract
Interleukin-15 receptor (IL-15R) and IL-2R have the same beta and gamma chains, but IL-15R has a specific alpha chain distinct from that of IL-2Ralpha, which is indispensable for the high affinity binding of IL-15. In the present study, we examined four IL-2-dependent adult T-cell leukemia (ATL) cell lines for their IL-15R expression. All cell lines bound IL-15, which was not inhibited by a 100-fold excess amount of IL-2, proliferated in response to IL-15 to the same degree as to the stimulation with IL-2, and were maintained without IL-2. The responses to 1L-15 were inhibited by the antibodies against IL-2R beta or gamma chains but was not by the IL-2R alpha chain antibody. [125I]-IL-15 exhibited a single high-affinity binding with an apparent kd of 0.17 nmol/L. Reverse transcription-coupled polymerase chain reaction (RT-PCR) showed that the cell lines had the mRNA of IL-15R alpha. The cell lines also had IL-15 mRNA. Despite the presence of IL-15 mRNA, the cell lines did not secrete IL-15, and the culture supernatants of fresh ATL cells and plasma from the patients did not contain a detectable amount of IL-15 with a few exceptional cases, although fresh ATL cells also responded to IL-15. These results suggest that ATL cells have the complete form of IL-15R and respond to IL-15. Such an IL-15-dependent cell proliferation mechanism might be used in the development of ATL and for the invasion and proliferation of ATL cells in the visceral organs.
- Published
- 1998
17. Integration patterns of HTLV-I provirus in relation to the clinical course of ATL: frequent clonal change at crisis from indolent disease.
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Tsukasaki K, Tsushima H, Yamamura M, Hata T, Murata K, Maeda T, Atogami S, Sohda H, Momita S, Ideda S, Katamine S, Yamada Y, Kamihira S, and Tomonaga M
- Subjects
- Aged, Blotting, Southern, Clone Cells pathology, Clone Cells virology, DNA, Viral analysis, Female, Humans, Leukemia-Lymphoma, Adult T-Cell etiology, Male, Middle Aged, Receptors, Antigen, T-Cell, alpha-beta genetics, Human T-lymphotropic virus 1 genetics, Leukemia-Lymphoma, Adult T-Cell pathology, Leukemia-Lymphoma, Adult T-Cell virology, Proviruses genetics, Virus Integration
- Abstract
We examined human T-lymphotropic virus type I (HTLV-I) DNA integration in 68 patients with adult T-cell leukemia/ lymphoma (ATL) by Southern blotting using EcoRI, which does not cut within the 9 kb of the genome and probes for pX and gag-pol region of HTLV-I. We detected defective proviral integration as a monoclonal band of various sizes with the pX but not with the gag-pol probe, or a monoclonal band of less than 9 kb with the pX probe, in 20 patients (29.4%). These were designated defective (D) type. With both probes, a single band greater than 9 kb was detected in 34 (50.0%), designated complete (C) type, and two or more bands greater than 9 kb, were designated multiple (M) type, in 14 (20.6%). Advanced age, a high LDH value, and hypercalcemia were more frequent in D type patients. The median survival time (MST) was 6.8, 24.4, and 33.3 months, for D, C, and M types, respectively (log rank P = .006). Among 52 sequentially examined patients, the HTLV-I integration patterns changed in 4 (7.5%). In three of these four, the rearrangements of the T-cell receptor (TCR)b gene concomitantly changed, suggesting the appearance of a new ATL clone. Another patient had the same rearrangement of the TCRb gene, indicating clonal evolution. The HTLV-I integration pattern changed at crisis from indolent to aggressive ATL in three patients. These findings suggested that the HTLV-I integration patterns have clinical implications in ATL pathophysiology. In contrast to the clonal evolution characteristic of the multistep carcinogenesis of most human malignancies, the frequent clonal change of ATL at crisis is a peculiar phenomenon, probably reflecting the emergence of multiple premalignant clones in viral leukemogenesis as suggested in Epstein-Barr virus associated lymphomagenesis in the immunocompromised host.
- Published
- 1997
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