Language：English   Publishing type：Research paper (scientific journal)  

The human herpes virus, Epstein-Barr virus (EBV), is a known oncogenic virus and plays important roles in life-threatening T/NK-cell lymphoproliferative disorders (T/NK-cell LPD) such as hypersensitivity to mosquito bite (HMB), chronic active EBV infection (CAEBV), and NK/T-cell lymphoma/leukemia. During the clinical courses of HMB and CAEBV, patients frequently develop malignant lymphomas and the diseases passively progress sequentially. In the present study, gene expression of CD16((-))CD56((+))-, EBV((+)) HMB, CAEBV, NK-lymphoma, and NK-leukemia cell lines, which were established from patients, was analyzed using oligonucleotide microarrays and compared to that of CD56(bright)CD16(dim/-) NK cells from healthy donors. Principal components analysis showed that CAEBV and NK-lymphoma cells were relatively closely located, indicating that they had similar expression profiles. Unsupervised hierarchal clustering analyses of microarray data and gene ontology analysis revealed specific gene clusters and identified several candidate genes responsible for disease that can be used to discriminate each category of NK-LPD and NK-cell lymphoma/leukemia.

DOI： 10.1080/10428194.2017.1304762

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Language：English   Publisher：WILEY-BLACKWELL  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The Polycomb repressive complex-2 members (EZH2, EED, SUZ12 and EZH1) are important regulators of haematopoiesis, cell cycle and differentiation. Over expression of EZH2 has been linked to cancer metastases and poor prognosis. Detailed information on the expression of other members in normal and neoplastic lymphoid tissue remains to be elucidated. Immunohistochemical and immunofluorescent analyses of 156 samples from haematopoietic neoplasms patients and 27 haematopoietic cell lines were used.
B-cell neoplasms showed a significant over-expression of EZH2, EED and SUZ12 in the aggressive subtypes compared to the indolent subtypes and normal tissue (p = 0.000-0.046) while expression of EZH1 was decreased in mantle cell lymphoma compared to normal tissue (p = 0.011). T/NK-cell neoplasms also showed significant over expression of EZH2, EED and SUZ12 (p = 0.000-0.002) and decreased expression of EZH1 (p = 0.001) compared to normal cells. EZH2 and EZH1 have opposite expression patterns both in normal and neoplastic lymphoid tissues as well as an opposite relation to Ki-67. These results were supported by western blotting analyses. Immunofluorescent staining revealed a difference in the intracellular localisation of EZH1 compared to other members.
These evidences suggest that EZH2 and EZH1 are important in the counter-balancing mechanisms controlling proliferation/resting of lymphoid cells. The disruption of the balanced EZH2/EZH1 ratio may play important roles in the pathogenesis of lymphomas.

DOI： 10.1016/j.pathol.2016.05.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Langerhans cell histiocytosis (LCH) is a proliferative disorder in which abnormal Langerhans cell (LC)-like cells (LCH cells) intermingle with inflammatory cells. Whether LCH is reactive or neoplastic remains a controversial matter. We recently described Merkel cell polyomavirus (MCPyV) as a possible causative agent of LCH and proposed interleukin-1 loop model: LCH is a reactive disorder with an underlying oncogenic potential and we now propose to test this theory by looking for acute markers of inflammation. We detected MCPyV-DNA in the peripheral blood cells of patients with high-risk organ-type (LCH-risk organ (RO) (+)) but not those with non-high-risk organ-type LCH (LCH-RO (-)); this difference was significant. LCH-RO (-) is further classified by its involvement of either a single organ system (SS-LCH) or multiple organ systems (MS-LCH). In patients with LCH-RO (-), MCPyV-DNA sequences were present in LCH tissues, and significant differences were observed between LCH tissues and control tissues associated with conditions such as dermatopathic lymphadenopathy and reactive lymphoid hyperplasia. Although MCPyV causes subclinical infection in nearly all people and 22 % of healthy adults will harbor MCPyV in their buffy coats, circulating monocytes could serve as MCPyV reservoirs and cause disseminated skin lesions.
Methods: Plasma sample from 12 patients with LCH-RO (-) (5 MS-LCH and 7 SS-LCH) and 5 non-LCH patients were analyzed by peptidomics. Mass spectrometry (MS) spectra were acquired and peptides exhibiting quantitative differences between MS-LCH and SS-LCH patients were targeted.
Results: One new candidate biomarker, m/z 3145 was selected and identified after obtaining a MS/MS fragmentation pattern using liquid chromatography-MS/MS. This peak was identified as a proteolytic fragment derived from interalpha- trypsin inhibitor heavy chain 4 (ITIH4, [PDB: Q14624]).
Conclusions: Peptidomics of LCH have revealed that the level of acute-phase ITIH4 distinguishes MS-LCH-RO (-) from SS-LCH-RO (-). Acute-phase proteins serve non-specific, physiological immune functions within the innate immune system. LCH may be a reactive disorder with both underlying neoplastic potential of antigen presenting cells harboring BRAF mutations and hyper-immunity of other inflammatory cells against MCPyV infection. Among LCH-RO (-), MCPyV-DNA sequences were present in both MS-LCH tissues and SS-LCH tissues without significant differences. ITIH4 may show that LCH activity or LCH subtypes correlates with the systemic or localized reactions of MCPyV infection.

DOI： 10.1186/s12014-015-9089-2

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：English   Publisher：BIOMED CENTRAL LTD  

We propose Langerhans cell histiocytosis (LCH) is an inflammatory process that is prolonged by mutations. We hypothesize that Merkel cell polyomavirus (MCPyV) infection triggers an interleukin-1 (IL-1) activation loop that underlies the pathogenesis of LCH. Langerhans cells (LCs) are antigen presenting cells in the skin. When LCs encounter exogenous antigens, they migrate from the epidermis into draining lymphoid tissues to initiate T-cell activity. It has been proposed that LC migration-related factors, including E-cadherin, matrix metalloproteinase, and Notch ligand induce LCH activity. We found that the tyrosine phosphatase SHP-1, which binds IL-1 receptor-associated kinase 1, is expressed at a significantly higher level in LCH affecting multiple organ systems (MS-LCH) than in LCH affecting a single organ system (SS-LCH). IL-1 stimulates T helper 17 cells and their signature cytokine IL-17 had been a matter of controversy. We detected higher levels of IL-17A receptor expression in MS-LCH than in SS-LCH and proposed an IL-17 endocrine model that could settle the controversy. IL-1 is the first cytokine secreted in response to sensitizers and promotes LC migration from sentinel tissues. Myeloid differentiation primary response 88 (MyD88), downstream of the IL-1 receptor, has functions in both RAS signaling and inflammation, leading to human cell transformation. In 2010, an activating mutation in the B-rapidly accelerated fibrosarcoma gene (BRAF) V600E was found in LCH. This BRAF mutation induces phosphorylation of the extracellular signal-regulated kinase (ERK) that may play an important role with MyD88 in LCH pathogenesis. However, phosphorylated ERK (pERK) is rapidly dephosphorylated by dual specificity phosphatase 6 (DUSP6), and limited proliferation is predicted in BRAF mutant cells. MyD88 binds pERK via its D-domain, thereby preventing pERK-DUSP6 interaction and maintaining ERK in an active, phosphorylated state. We detected MCPyV-DNA in the peripheral blood cells of two out of three patients with LCH in high-risk organs but not in those of patients with LCH in non-high-risk organs (0/12; P = .029). MCPyV infection can trigger precursor LCH cells with BRAF mutation to produce IL-1; the IL-1 loop is amplified in all LCH subclasses. Our model indicates both BRAF mutation and IL-1 loop regulation as potential therapeutic targets.

DOI： 10.1186/s12964-015-0092-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

A cell line named PRU-1, derived from a Langerhans cell (LC) histiocytosis (LCH) skull lesion of a 7-year-old boy, was established and characterized. PRU-1 is an adherent spindle-shaped cell line that shows no Birbeck granules on electron microscopy. Flow cytometric analysis of cells collected from the early seventh passage showed no LC phenotypes of CD1a and S100 protein. Immunostaining of PRU-1 cells also revealed no expression of LC markers but showed expression of CD11c, CD54 (ICAM-1) and CD68, which was also observed in some peripherally located cells of the original LCH lesion. The PRU-1 cells stained positive for factor XIIIa and negative for CD34, suggesting a dermal dendritic cell phenotype. Cytogenetic analyses revealed abnormalities such as 39, XY, -2, -4, -8, -12, -12, -14, add (18)(q21), 20, +mar and 44, XY, -11, -14, add(18)(q21). TCR rearrangement in the PRU-1 cells was not amplified by PCR. Tumorigenicity was not proven by xenografting into SCID mice. A conditioned medium from PRU-1 culture induced the proliferation of peripheral blood lymphocytes as well as the activation of monocytes from a healthy donor into CD1a-positive LC-like cells. Because the phenotypic characteristics of PRU-1 differed from those of CD1a-positive abnormal LC-like cells (LCH cells), it was likely that the PRU-1 cells were derived from peripherally located cells of the LCH lesion rather than LCH cells. LCH has been regarded as a type of granulomatous neoplasm with several intermingled inflammatory cells and influenced by stimuli such as Merkel cell polyomavirus (MCPyV) infection or cigarette smoking. However, in the PRU-1 cells, MCPyV-DNA was not detected by PCR. Stromal cell-like PRU-1 cells are likely to produce some growth or differentiation factors, which may play important roles in LCH lesion formation, cell maintenance and LC-like cell induction.

DOI： 10.3892/or.2014.3567

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INFORMA HEALTHCARE  

While the use of polymerase chain reaction (PCR)-based clonality analysis of formalin-fixed paraffin-embedded (FFPE) tissue has recently become widespread, the detection sensitivity for lymphoma subtypes using FFPE samples is not well known. Here, we analyzed T-cell receptor gamma chain (TCRG) gene rearrangement clonality in 100 cases of T-or natural killer (NK)/T-cell lymphoma and examined detection sensitivity according to lymphoma subtype. Clonality was detected in approximately 80% of the major T-cell lymphoma subtypes: peripheral T-cell lymphoma, not otherwise specified, 84% (21/25 cases); angioimmunoblastic T-cell lymphoma, 71% (15/21 cases); and adult T-cell leukemia/lymphoma, 80% (8/10 cases). The number of clonal peaks differed according to subtype. TCRG gene rearrangement was not detected in 63 cases of B-cell lymphoma or reactive lesions. Thus, clonality analysis can effectively and reliably detect TCRG gene rearrangement in T-cell lymphoma cases and could, therefore, be a useful diagnostic tool in routine practice.

DOI： 10.3109/10428194.2013.871634

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Langerhans cell (LC) sarcoma (LCS) is a high-grade neoplasm with overtly malignant cytologic features and an LC phenotype. We very recently suggested that LC behaves as a reservoir for common dermotropic Merkel cell polyomavirus (MCPyV) and determined the relationship between LC histiocytosis (LCH), which has an underlining oncogenic capacity, and MCPyV as a trigger for a reactive process rather than a neoplastic process. We propose LC to be a reservoir for MCPyV and hypothesize that some LCS subtypes may be related to the MCPyV agent.
Findings: We examined seven LCS tissues using multiplex quantitative PCR (Q-PCR) and immunohistochemistry with anti MCPyV large-T (LT) antigen antibody. High viral loads of MCPyV DNA sequences (viral load = relative levels of MCPyV) were detected (0.328-0.772 copies/cell (Merkel cell carcinoma (MCC) = 1.0)) using Q-PCR in 43% (3/7) tissues, but LT antigen expression was not observed (0/7).
Conclusions: Frequent MCPyV-DNA amplification suggests that LCS in some patients may be related to MCPyV infection. Moreover, the higher viral load of LCS (median, 0.453 copies/cell) than low load of LCH (0.003, median of 12 cases) (P < 0.01) may suggest a virally induced tumorigenic process in some LCS. Although the absence of LT antigen expression may indicate a different role for MCPyV in this pathology, some subtypes of LCS may develop in the background of MCPyV-infected LC. To the best of our knowledge, this is the first report on the relationship between MCPyV and LCS. The recent discovery of MCPyV opened new therapeutic avenues for MCC. These data open novel possibilities for therapeutic interventions against LCS.

DOI： 10.1186/1750-9378-9-15

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Viral infections have been implicated as a cause of complex seizures in children. The pathogenic differences in complex seizures due to influenza A(H1N1)pdm09 or rotavirus gastroenteritis remain unclear. This study analyzed the gene expression profiles in the peripheral whole blood from pediatric patients with complex seizures due to influenza A(H1N1)pdm09 or rotavirus gastroenteritis. The gene expression profiles of ten patients (five with seizures and five without) with influenza A(H1N1)pdm09 and six patients (three with seizures and three without) with rotavirus gastroenteritis were examined. Gene expression profiles in the whole blood were different in complex seizures due to influenza A(H1N1)pdm09 or rotavirus gastroenteritis. Transcripts related to the immune response were significantly differentially expressed in complex seizures with influenza A(H1N1)pdm09, and transcripts related to the stress response were significantly differentially expressed in complex seizures with rotavirus gastroenteritis. Pathway analysis showed that the mitogen-activated protein kinases in the T cell receptor signaling pathway were activated in complex seizures due to influenza A(H1N1)pdm09. Dysregulation of the genes related to immune response or stress response could contribute to the pathogenic differences of the complex seizures due to influenza A(H1N1)pdm09 or rotavirus gastroenteritis.

DOI： 10.1007/s13365-013-0231-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Langerhans cell histiocytosis (LCH) is a group of granulomatous disorders in which abnormal Langerhans cells proliferate as either a localized lesion in a single bone or disseminated disease involving two or more organs or systems. Because the different LCH forms exhibit significantly elevated levels of inflammatory molecules, including pro-inflammatory cytokines and tissue-degrading enzymes, we investigated for a possible viral trigger in LCH pathogenesis. We looked for Merkel cell polyomavirus (MCPyV) in peripheral blood cells and tissues using quantitative real-time PCR and immunohistochemistry staining with anti-MCPyV large T-antigen antibody. Our findings revealed elevated amounts of MCPyV DNA in the peripheral blood cells of 2 of 3 patients affected by LCH with high-risk organ involvement (RO+) and absence of MCPyV DNA in the blood cells in all 12 LCH-RO-patients (P = .029). With lower viral loads (0.002-0.033 copies/cell), an elevated number of MCPyV DNA sequences was detected in 12 LCH tissues in comparison with control tissues obtained from patients with reactive lymphoid hyperplasia (0/5; P = .0007), skin diseases not related to LCH in children younger than 2 years (0/11; P = .0007), or dermatopathic lymphadenopathy (5/20; P = .0002). The data, including frequent but lower viral loads and low large-T antigen expression rate (2/13 LCH tissues), suggest that development of LCH as a reactive rather than a neoplastic process may be related to MCPyV infection. (C) 2014 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2013.05.028

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

A close relationship between cell death and pathological calcification has recently been reported, such as vascular calcification in atherosclerosis. However, the roles of cell death in calcification by osteoblast lineage have not been elucidated in detail. In this study, we investigated whether cell death is involved in the calcification on osteoblastic differentiation of human bone marrow mesenchymal stem cells (hMSC) under osteogenic culture in vitro. Apoptosis and necrosis occurred in an osteogenic culture of hMSC, and cell death preceded calcification. The generation of intracellular reactive oxygen species, chromatin condensation and fragmentation, and caspase-3 activation increased in this culture. A pan-caspase inhibitor (Z-VAD-FMK) and anti-oxidants (Tiron and n-acetylcysteine) inhibited osteogenic culture-induced cell death and calcification. Furthermore, calcification was significantly promoted by the addition of necrotic dead cells or its membrane fraction. Spontaneously dead cells by osteogenic culture and exogenously added necrotic cells were surrounded by calcium deposits. Induction of localized cell death by photodynamic treatment in the osteogenic culture resulted in co-localized calcification. These findings show that necrotic and apoptotic cell deaths were induced in an osteogenic culture of hMSC and indicated that both necrotic and apoptotic cells of osteoblast lineage served as nuclei for calcification on osteoblastic differentiation of hMSC in vitro. Copyright (c) 2013 John Wiley & Sons, Ltd.

DOI： 10.1002/cbf.2974

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Polycomb group (PcG) proteins are important for the regulation of hematopoiesis by regulating chromatin compaction and silencing genes related to differentiation and cell cycle. Overexpression of enhancer of zeste homologue 2 (Ezh2) and Bmi-1/PCGF4 has been implicated in solid organ cancers, while Mel-18/PCGF2 has been reported as a tumor suppressor. Detailed expression profiles of PcG proteins and their diagnostic significance in malignant lymphomas are still unknown. In this study, we analyzed the expression levels of Ezh2, Bmi-1, Mel-18, and Ki67 in 197 Hodgkin's and non-Hodgkin's lymphoma patient samples and in lymphoma cell lines using immunohistochemistry, fluorescent immunocytochemistry, and Western blotting. Immunohistochemical staining showed that Ezh2 expression was significantly increased in aggressive compared to indolent subtypes of B cell neoplasms (P = 0.000-0.030), while no significant differences in Bmi-1 expression were found between these subtypes. Compared to the normal counterpart, T cell lymphomas showed significant overexpression of Bmi-1 (P = 0.011) and Ezh2 (P = 0.000). The Ki67 labeling index showed a positive correlation with Ezh2 expression in B cell lymphomas (correlation coefficient (Co) = 0.983, P = 0.000) and T/NK cell lymphomas (Co = 0.629, P = 0.000). Fluorescent immunohistochemical staining showed coexpression of Ezh2 and Ki67 in the same tumor cells, indicating that Ezh2 expression correlates with cell proliferation. Both B and T/NK cell neoplasms showed low expression of Mel-18 and high expression of both Bmi-1 and Ezh2. In conclusion, in aggressive lymphoma variants, Ezh2 is strongly expressed and polycomb repressive complex PRC1.4 dominates over PRC1.2. Coexpression of Bmi-1 and Ezh2 is a characteristic of aggressive lymphomas. Ezh2 correlates with the proliferation and aggressive nature of non-Hodgkin's lymphomas.

DOI： 10.1007/s00428-013-1428-y

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Background: The pathogenic mechanisms underlying influenza A(H1N1)pdm09-associated central nervous system (CNS) manifestations and pneumonia remain unclear. This study examined A(H1N1)pdm09 host responses using gene expression profiles of patients' peripheral blood. Methods: Sixteen A(H1N1)pdm09-infected children in three groups were examined: a CNS group, with convulsion and altered consciousness (n = 6)
a pneumonia (Pneu) group (n = 5)
and a group of infected control patients (n = 5). The signal ratios of the acute to recovery phases in CNS or Pneu were analyzed versus those of the control. Results: The CNS (619 transcripts) and Pneu (656 transcripts) groups had significantly increased signal ratios compared to the control group. Regarding the increased ratios of transcripts shown by multiple probes, contactin-associated protein-like 3 transcripts, oleoyl-ACP hydrolase transcripts, and interleukin 1 type 1 receptor were observed in CNS and Pneu. Increased ratios of prostaglandin-endoperoxide synthase 2 and α-synuclein were characteristic of CNS. Alkaline phosphatase and the Fc fragment of IgA receptor were characteristic of Pneu. Regarding enriched gene ontology terms, 'response to lipopolysaccharide', 'innate immune response', and 'intrinsic to membrane' were observed commonly in CNS and Pneu. Enriched gene ontology terms related to 'hemoglobin' and 'hemostasis' were, respectively, characteristic of CNS and Pneu. Conclusion: These symptom-associated transcripts might be some clues to the pathogenesis of the A(H1N1)pdm09 infection. © 2013 Japan Pediatric Society.

DOI： 10.1111/ped.12139

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Language：Japanese  

DOI： 10.4044/joma.125.103

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Other Link： http://ousar.lib.okayama-u.ac.jp/50806

Language：English   Publisher：NATURE PUBLISHING GROUP  

DOI： 10.1038/modpathol.2013.118

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Langerhans cell histiocytosis (LCH) is a lymphoproliferative disorder consisting of abnormal Langerhans cell-like cells and other lymphoid cells. LCH presents as either a multisystem LCH (LCH-MS) or a single-system LCH (LCH-SS). Currently, neither the pathogeneses nor the factors that define these disease subclasses have been elucidated. The interleukin (IL)-17A autocrine LCH model and IL-17A-targeted therapies have been proposed and have engendered much controversy. Those authors showed high serum IL-17A levels in LCH and argued that serum IL-17A-dependent fusion activities in vitro, rather than serum IL-17A levels, correlated with LCH severity (i.e. the IL-17A paradox). In contrast, others could not confirm the IL-17A autocrine model. So began the controversy on IL-17A, which still continues. We approached the IL-17A controversy and the IL-17A paradox from a new perspective in considering the expression levels of IL-17A receptor (IL-17RA). We detected higher levels of IL-17RA protein expression in LCH-MS (n = 10) as compared to LCH-SS (n = 9) (P = 0.041) by immunofluorescence. We reconfirmed these data by re-analyzing GSE16395 mRNA data. We found that serum levels of IL-17A were higher in LCH (n = 38) as compared to controls (n = 20) (P = 0.005) with no significant difference between LCH subclasses. We propose an IL-17A endocrine model and stress that changes in IL-17RA expression levels are important for defining LCH subclasses. We hypothesize that these IL-17RA data could clarify the IL-17A controversy and the IL-17A paradox. As a potential treatment of LCH-MS, we indicate the possibility of an IL-17RA-targeted therapy.

DOI： 10.1007/s00428-012-1360-6

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Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2012-3132

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Language：Japanese   Publisher：(一社)日本病理学会  

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DOI： 10.1038/modpathol.2012.127

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Nitrogen-containing bisphosphonates (BPs) are antiresorptive drugs used for the treatment of metabolic bone diseases. Bone marrow stromal cells such as mesenchymal stem cells (MSCs) and MSC-derived osteoblasts that originate from MSCs are known to regulate osteoclast differentiation and activation via the expression of receptor activator of NF-kappa B ligand (RANKL). Although the effects of nitrogen-containing BPs on osteoclasts and osteoblasts have been well investigated, their effects in MSCs have not been clarified. In this study, we investigated the effects of risedronate (RIS), a nitrogen-containing BP, on osteoblast differentiation, RANKL expression and apoptosis in human and rat MSCs. RIS suppressed the formation of mineralized nodules and mRNA expression of differentiation marker genes such as bone sialoprotein and osteocalcin in MSC-derived osteoblasts. The RANKL expression induced by 1,25-(OH)(2) vitamin D(3) was not affected by RIS in human MSC-derived osteoblasts. In addition, treatment with high-concentration RIS induced chromatin condensation, an apoptosis feature, in MSCs. RIS-induced chromatin condensation was suppressed by a pan-caspase inhibitor zVAD-FMK and a cell-permeable isoprenoid analogue geranylgeraniol. These results indicate that RIS suppressed osteoblast differentiation and induced caspase-and isoprenoid depletion-dependent apoptosis and suggest that the antiresorptive effect of RIS is not mediated by a decrease in the RANKL expression in MSC-derived osteoblasts.

DOI： 10.1111/j.1742-7843.2011.00685.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Langerhans cell histiocytosis (LCH) is a proliferative disorder of Langerhans cell (LC)-like CD1a-positive cell (LCH cell) with unknown causes. LCH consists of two subtypes: single-system LCH (LCH-SS) with favorable prognosis and multisystem LCH (LCH-MS) with poor prognosis. LCH has been indicated as a neoplastic disorder from monoclonal characteristics of LCH cells. This study aimed to investigate an expression of tyrosine phosphatase SHP-1 in LCH, since its expression levels were variously reported in many tumors, overexpression in ovarian cancers (a candidate oncoprotein), and downregulation by methylation in gastric cancers, prostate cancers, malignant lymphomas, and leukemias (a putative tumor suppressor). By immunohistochemistry (IHC), the SHP-1 expression in LCs and LCH cells was compared in LCH (two subtypes: LCH-SS = 21, LCH-MS = 12), dermatopathic lymphadenopathy (DLA) (n = 9) and normal epidermal LCs (n = 3) near LCH lesion. IHC results were analyzed semiquantitatively using a Photoshop software. The mean intensity score (IS) of DLA, LCH-SS, LCH-MS, and LCs were 47, 100, 139, and 167 (in arbitrary unit), respectively. The IS had significant differences among LCH-SS, LCH-MS, and DLA (p < 0.01). SHP-1 is expressed significantly higher in LCH-MS than in LCH-SS. SHP-1 can be a progression marker of LCH. SHP-1 is also useful for differential diagnosis between LCH in lymph nodes and DLA.

DOI： 10.1007/s00428-011-1090-1

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Language：Japanese   Publisher：(一社)日本リンパ網内系学会  

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Although cancers have been thought to be predominantly driven by acquired genetic changes, it is becoming clear that microenvironment-mediated epigenetic alterations play important roles. Aberrant promoter hypermethylation is a prevalent phenomenon in human cancers as well as malignant lymphoma/leukemia. Tumor suppressor genes become frequent targets of aberrant hypermethylation in the course of gene-silencing due to the increased and deregulated DNA methyltransferases (DNMTs). The purpose of this article is to review the current status of knowledge about the contribution of cumulative epigenetic abnormalities of the host genes after microbial and virus infection to the crisis and progression of malignant lymphoma/leukemia. In addition, the relevance of this knowledge to malignant lymphoma/leukemia assessment, prevention and early detection will be discussed. © 2011 by the authors
licensee MDPI, Basel, Switzerland.

DOI： 10.3390/cancers3010568

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

The CD79 molecule, encoded by the CD79a and CD79b genes, is a signaling unit of the B-cell receptor complex, which transmits signals of B-cell activation, growth, and differentiation. They are B-cell-specific and expressed at most stages of B-cell development. Although plasma cells have been believed to lack these gene products, the regulation of CD79 expression in plasma cells is still controversial. In particular, the regulation of CD79b expression remains unclear. We sought to examine CD79b expression in normal and neoplastic plasma cells by immunohistochemical analysis. Out of the 23 clinical samples and 11 cell lines of plasma cell myeloma (PCM), none of the clinical samples and only 1 of 11 cell lines expressed CD79b immunohistologically, whereas non-neoplastic plasma cells in reactive hyperplastic lymph nodes exhibited loss of CD79b protein expression. This finding is quite different from our previous report on CD79a. Not only immunocytochemistry, but also RT-PCR and Western blot analysis of PCM cell lines gave identical results. Interestingly, we detected mRNA transcripts of CD79b in PCM cell lines, although protein translation was lacking. These findings suggest that expression of CD79b is downregulated in both plasma cells and plasma cell myeloma, and this process is possibly under post transcriptional regulation.

DOI： 10.1111/j.1440-1827.2010.02634.x

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC INVESTIGATIVE PATHOLOGY, INC  

Aberrant CpG island methylation contributes to the pathogenesis of various malignancies. However, little is known about the association of epigenetic abnormalities with multistep tumorigenic events in adult T cell leukemia/lymphoma (ATLL). To determine whether epigenetic abnormalities induce the progression of ATLL, we analyzed the methylation profiles of the SHP1, p15, p16, p73, HCAD, DAPK, hMLH-1, and MGMT genes by methylation specific PCR assay in 65 cases with ATLL patients. The number of CpG island methylated genes increased with disease progression and aberrant hypermethylation in specific genes was detected even in HTLV-1 carriers and correlated with progression to ATLL. The CpG island methylator phenotype (CIMP) was observed most frequently in lymphoma type ATLL and was also closely associated with the progression and crisis of ATLL. The high number of methylated genes and increase of CIMP incidence were shown to be unfavorable prognostic factors and correlated with a shorter overall survival by Kaplan-Meyer analysis. The present findings strongly suggest that the multistep accumulation of aberrant CpG methylation in specific target genes and the presence of CIMP are deeply involved in the crisis, progression, and prognosis of ATLL, as well as indicate the value of CpG methylation and CIMP for new diagnostic and prognostic biomarkers. (Am J Pathol 2010, 176:402-415; DOI: 10.2353/ajpath.2010.090236)

DOI： 10.2353/ajpath.2010.090236

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Language：Japanese   Publisher：Fukuoka University  

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Other Link： http://id.nii.ac.jp/1316/00002095/

Language：English   Publisher：WILEY-LISS  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC INVESTIGATIVE PATHOLOGY, INC  

Reactive oxygen species (ROS) production is an antimicrobial response to pathogenic challenge that may, in the case of persistent infection, have deleterious effects on the tissue of origin. A rat periodontal disease model was used to study ROS-induced chronic epithelial inflammation and bone loss. Lipopolysaccharide (LPS) was applied for 8 weeks into the gingival sulcus, and histological analysis confirmed the onset of chronic disease. junctional epithelium was collected from healthy and diseased animals using laser-capture microdissection, and expression microarray analysis was performed. Of 19,730 genes changed in disease, 42 were up-regulated >= 4-fold. Three of the top 10 LPS-induced genes, monoamine oxidase B (MAO/B) and flavin-containing monooxygenase 1 and 2, are implicated in ROS signaling. LPS-associated induction of the ROS mediator H(2)O(2) as well as MAO/B and tumor necrosis factor (TNF)-alpha levels were validated in the rat histological sections and a porcine junctional epithelial cell culture model. Topical MAO inhibitors significantly counteracted LPS-associated elevation of H(2)O(2) production and TNF-alpha expression in vivo and in vitro, inhibited disease-associated apical migration and proliferation of junctional epithelium and inhibited induced systemic H(2)O(2) levels and alveolar bone loss in vivo. These results suggest that LPS induces chronic wounds via elevated MAO/B-mediated increases in H(2)O(2) and TNF-alpha activity by epithelial cells and is further associated with more distant effects on systemic oxidative stress and alveolar bone loss. (Am J Pathol 2009,175:1398-1409; DOI: 10.2353/ajpath.2009.090108)

DOI： 10.2353/ajpath.2009.090108

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

Aberrant DNA hypermethylation is an important mechanism for the inactivation of tumor-related genes in human tumors. Gastric mucosa-associated lymphoid tissue (MALT) lymphomas arise from Helicobacter pylori-associated chronic gastritis: most patients are H. pylori-positive and eradication therapy is highly effective. In the present study, we used methylation-specific PCR to analyze the DNA methylation status of 11 tumor-related genes (Kip2, p16, hMLH-1, p15, p73, MGMT, DAPK, MINT1, MINT2, MINT31 and HCAD) in 21 specimens of MALT lymphoma, 5 specimens of MALT lymphoma with large cell component (high-grade MALT lymphoma), 15 specimens of diffuse large B-cell lymphoma (DLBCL), 8 specimens of complete remission of MALT lymphoma after eradication therapy, 5 specimens with no evidence of malignancy and PBMCs from 10 healthy donors. The average number of methylated genes was significantly greater in gastric lymphomas as compared to normal controls (P<0.001). The CpG island methylator phenotype (CIMP) was observed in 93.3% (14/15) of DLBCLs, 100% (5/5) of high-grade MALT lymphomas and 61.9% (13/21) of MALT lymphomas; in contrast, CIMP was not found in the control group (0%). The average number of methylated genes and the CIMP incidence significantly increased with H. pylori infection. Furthermore, aberrant CpG methylation of specific genes, such as p16, MGMT and MINT31, was consistently associated with H. pylori infection. These findings strongly suggest that H. pylori infection causes the aberrant DNA hypermethylation of specific genes and induces CIMP, which is an important epigenetic mechanism for the development and progression of gastric MALT lymphoma; additionally, our findings provide new epigenetic markers.

DOI： 10.3892/ijo_00000366

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Language：English  

Although most follicular lymphomas are believed to be of nodal origin, they sometimes originate from the duodenum. We have reported that the latter differ from nodal follicular lymphomas in having lower clinical stages and uniformly low histological grades, along with variable region of immunoglobulin heavy chain gene (VH) usage that is more similar to mucosa-associated lymphoid tissue (MALT) lymphomas. Little is known, however, about whether they possess other characteristics of nodal follicular lymphomas, particularly ongoing mutations with follicular dendritic cells. We examined 17 cases for which PCR identified the monoclonal bands of the immunoglobulin gene. The duodenal cases showed ongoing mutations, but they lacked activation-induced cytidine deaminase (AID) expression, a statistically significant difference from the nodal cases (P<0.001), and their follicular dendritic cell networks were disrupted. Moreover, not only were VH deviations observed but also they used very restricted VH genes. Although the mechanisms of ongoing mutation without AID and follicular dendritic cell were not clarified, restricted VH usage strongly suggested that antigen stimulation was involved, and that was similar to MALT lymphomas. In conclusion, duodenal follicular lymphomas were shown to be unique, in that they had ongoing hypermutations such as nodal cases, but the mechanisms involved in the hypermutation were quite different; furthermore, restricted VH usage suggested a strong similarity to the antigen-dependent origin of MALT lymphomas.

DOI： 10.1038/modpathol.2009.51

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Language：Japanese   Publisher：(一社)日本リンパ網内系学会  

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：English   Publisher：The Japanese Society for Lymphoreticular Tissue Research  

Until now, no method has been available to discriminate mature plasmacytoid DC (pDC) from myeloid DC (mDC) immunohistochemically. In this study, we report that these DC-subsets can be distinguished in routine pathological sections. Immature and mature monocyte-derived DCs (MoDCs) were S100 calcium binding protein B (S100B)⁺, while pDCs generated from pDC-precursors were S100B^-. In contrast, both mature MoDC and pDC were fascin⁺. Epidermal Langerhans cells (LCs) were S100B⁺/fascin^-. Although the majority of DCs were S100B⁺/fascin⁺ in the dermis with nonspecific inflammation, dermal DCs were mostly S100B^-/fascin⁺ in psoriasis vulgaris, in which type I interferon secreted by pDC-precursors is thought to play a major role. S100B⁺/fascin⁺ DCs were accumulated in the superficial lymph node (LN), while they were scarce in the deep LN. In the superficial LN with dermatopathic lymphadenitis, a large number of S100B⁺/fascin⁺ DCs were accumulated in the T-zones, where numerous LC-derived DCs are accumulated. In contrast, almost all DCs were S100B^-/fascin⁺ in the superficial LN with Kikuchi's lymphadenitis, in which numerous pDC-precursors are known to be present. In contrast to the superficial LN, the deep LN contained numerous S100B^-/fascin⁺ DCs and a few S100B⁺ DCs. Thus, the distributions of S100B⁺ DC or S100B^-/fascin⁺ DC correspond to the putative distribution of mDC or mature pDC, respectively. [J Clin Exp Hematopathol 49(1) : 23-31, 2009]

DOI： 10.3960/jslrt.49.23

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Other Link： http://search.jamas.or.jp/link/ui/2009344727

Language：Japanese   Publisher：(一社)日本リンパ網内系学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：B M J PUBLISHING GROUP  

Background: Follicular lymphomas occasionally arise in the extra-nodal organs and are frequently found in the duodenum. They are often localised tumours with multiple polyps around the ampulla of Vater.
Aims: To examine a IgH/bcl-2 hybrid gene and VH gene to investigate the nature of the lymphoma cells and how they differ from nodal follicular lymphomas and MALT lymphomas.
Methods: Of 40 patients reported previously, 35 with duodenal follicular lymphoma were studied in detail with respect to clinicopathological characteristics.
Results: 37/40 patients were in clinical stage I (n= 30) or stage II (n= 7). Clonal immunoglobulin gene rearrangement was detected in 53.3% of examined cases, and rearrangement of IgH/bcl-2 gene at the major break point was detected in 27% of cases. Three of 8 examined cases were VH4 (38%); 2 out of them were VH4-34. As VH4 deviation is one of the common characteristics of MALT lymphomas and 2/3 were identical, duodenal follicular lymphomas have a similar aetiology to MALT lymphomas. Clinical course was also similar to that of MALT lymphomas.
Conclusions: Results suggest that duodenal follicular lymphomas have intermediate characteristics of MALT lymphomas and nodal follicular lymphomas.

DOI： 10.1136/jcp.2007.049825

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

Although adult T-cell leukemia/lymphoma (ATLL) is initiated by infection with human T-cell leukemia virus (HTLV-1), many other factors are thought to be required for the progression from indolent ATL to aggressive ATLL. The drs gene was onginally isolated as a novel suppressor gene of v-src transformation and was shown to induce apoptosis in human cancer cells. To investigate the involvement of drs downregulation in the progression of ATLL, we examined the expression of drs in smoldering, chronic and aggressive ATLL, and found that drs expression was markedly reduced in clinically aggressive ATLL. In aggressive ATLL cell lines, expression of drs mRNA was not detected, although expression of drs mRNA was detected in T-cell lines infected with HTLV-1. A correlation between drs downregulation and expression of the Tax gene was not observed in these T-cell lines. Furthermore, introduction of drs into an ATL cell line, HUT102, by retrovirus vector suppressed the colony formation of the cells in soft agar and enhanced apoptotic cell death of the cells under low serum culture conditions. These results indicate that downregulation of drs is closely linked to the progression of ATLL, independently of Tax expression, suggesting that drs may suppress the progression of ATLL via enhancing apoptosis.

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Language：English   Publisher：MARY ANN LIEBERT INC  

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It remains unclear whether or not diffuse large B-cell lymphomas of extranodal sites arise from mucosa-associated lymphoid tissue (MALT) lymphomas. We studied the clinicopathological features of MALT lymphoma and diffuse large B-cell lymphoma in the thyroid gland, with special reference to VH usage of immunoglobulin gene rearrangement, to clarify the relationships between these two types of lymphomas. In addition, t(11; 18) (q21; q21) translocation was examined by multiplex reverse transcription-polymerase chain reaction. We examined 58 patients with primary thyroid lymphoma: 31 (male seven and female 24) with MALT lymphoma and 27 (male three and female 24) with diffuse large B-cell lymphoma. Interestingly, the sequence of VH genes revealed that the two subtypes differed significantly in their use of the VH4 family (P < 0.05). Of the seven MALT lymphomas, three used the VH4 family and the other four used the VH3 family, whereas eight out of nine diffuse large B-cell lymphoma used the VH3 family, one used the VH1 family, and none used the VH4 family. It was also interesting that, in one diffuse large B-cell lymphoma patient with MALT lymphoma, the diffuse large B-cell lymphoma component used the VH3 family and the MALT lymphoma component used the VH4 family. These data imply that, in a subset of cases, these two subtypes do not share a common origin and that at least some diffuse large B-cell lymphomas have a de novo origin. No t(11; 18) (q21; q21) was detected in thyroid lymphomas, which are different from MALT lymphoma of the stomach, lungs, large intestine and ocular adnexa. This strongly indicated that the presence of t(11; 18) (q21; q21) in MALT lymphoma is organ-specific.

DOI： 10.1038/modpathol.3800692

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive form of human leukemia/lymphoma. Although this disease is initiated by infection with human T-lymphotropic virus type 1 (HTLV-1), many HTLV-1 carriers survive for a long period without aggressive illness, suggesting that other factors may play roles in the progression of ATLL to an aggressive state. However, the mechanism involved in this progression still remains unclear. Previously, we have reported that ASY/Nogo mRNA was markedly down-regulated in human small-cell lung carcinomas, whereas it was expressed in normal tissues and other lung carcinomas, such as adenocarcinoma and squamous cell carcinoma. To understand whether or not ASY/Nogo gene is involved in the progression of ATLL, we examined the expression of ASY/Nogo mRNA in smoldering, chronic and aggressive ATLL, and found that the expression level of ASY/Nogo mRNA was markedly reduced in clinically aggressive ATLL. HTLV-1 Tax expression was not affected by the down-regulation of ASY/Nogo mRNA. These results indicate that the ASY/Nogo gene may act as a suppressor against ATLL progression, independent of Tax expression. (c) 2006 Wiley-Liss, Inc.

DOI： 10.1002/ijc.22011

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

The lymphoepithelial symbiosis (LES) of the human palatine tonsil is composed of spindle- or starshaped epithelial cells forming a loose meshwork, containing numerous lymphocytes and dendritic cells (DCs). In the present study, we immunohistochemically characterized DCs in the LES (LES-DCs). LES-DCs were phenotypically immature DCs that were S100 beta+, fascin-, HLA-DR+, CD1a-, CD80-, CD83-, CD86-, and CD123-. The most characteristic feature of LES-DCs was that they contacted many B cells, which were mostly IgM+ IgD+ resting naive B cells. Langerhans cells (LCs) located in the nonsymbiotic squamous epithelium were immature DCs that were S100 beta+, fascin-, and CD1a+ and did not contact lymphocytes. In contrast to LES-DCs, interdigitating dendritic cells (IDCs) in the T zone were mature DCs that were HLA-DR+, CD1a-, fascin+, CD80+, CD83+, and CD86+ and contacted numerous CD4+ T cells. Two subsets of IDC, S100 beta+ fascin+ IDC (IDC-1) and S100 beta- fascin+ IDC (IDC-2), were identified, and the majority of IDCs are IDC-2. In contrast to IDCs, which were distributed in the T-cell area in groups, LES-DCs were distributed along the crypt as if forming a barrier. These findings suggest that LES-DCs are a novel type of DC playing an important role in the induction of humoral immune response against incoming air- or food-borne pathogenic antigens.

DOI： 10.1007/s00428-005-0085-1

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Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

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Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

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Language：English  

We investigated the relationship of gastric mucosa-associated lymphoid tissue (MALT) lymphoma tumorigenesis to Helicobacter pylori infection, the t (11;18) translocation, and alterations in cell cycle regulators. We sought to assess the implications of altered expression of p27(Kip1), a cyclin-dependent kinase inhibitor, on high-grade transformation and responsiveness to eradication therapy. We used immunohistochemistry to examine p27(Kip1), p53, and Ki-67 expression in 23 MALT lymphomas, five diffuse large B-cell lymphomas (DLBCLs), and four DLBCLs with associated MALT lymphoma. All of the MALT lymphomas were positive for p27(Kip1) expression and negative for p53 with a low Ki-67 index, regardless of the sensitivity of these cells to eradication. All DLBCLs were negative for p27(Kip1) and positive for p53, exhibiting a high Ki-67 index. In DLBCLs with MALT lymphoma, p27(Kip1) expression was absent from both the MALT and large cells components. In all of these lymphomas, the MALT components were negative for p53 and displayed a low Ki-67 index, while the large cell components were positive for p53 with a high Ki-67 index. The expression patterns of the DLBCLs differed significantly from those of the MALT lymphomas. p27(Kip1) was not detected in either component of DLBCL with MALT lymphoma, suggesting that decreased expression of p27(Kip1) in the MALT component may be related to high-grade transformation. Thus, p27(Kip1) expression in morphological MALT lymphomas could be useful tool to predict high-grade transformation to DLBCL.

DOI： 10.3960/jslrt.46.25

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Language：English  

PURPOSE: Bcl-2 is a model apoptosis suppressor postulated to promote tumorigenesis. Recently, it has been reported that Bcl-2 undergoes phosphoregulation of its Ser70 to substantially alter its molecular function. Previous studies further suggest that such phospho-Bcl-2 regulation may influence tumor progression in colorectal and other cancers; however, phosphorylation status of the Ser70 of Bcl-2 (pSer70) in vivo in tumors remains obscure. To elucidate this question that may suggest the biological role, we molecularly screened a panel of human colorectal adenomas and adenocarcinomas for endogenous expression of pSer70 Bcl-2. EXPERIMENTAL DESIGN: An antibody specific against pSer70 Bcl-2 was generated for thorough immunohistochemical examination of paraffin-embedded tumor specimens, allowing detection of the endogenously expressed antigen among a range of Bcl-2-positive colorectal neoplasms, including 75 tubular adenomas, 114 adenocarcinomas, and 15 cases of cancer in adenomas. RESULTS: Loss of pSer70 Bcl-2 expression was observed in adenocarcinomas in a differentiation-dependent manner (positivities: well differentiated 63%, moderately differentiated 52%, and poorly differentiated 12%), whereas tubular adenomas maintained their expression (positivity 88%). Interestingly, an inverse correlation was found between expression of pSer70 Bcl-2 and Ki-67 antigen in those cases of cancer in adenoma (P < 0.01). It was further observed that loss of pSer70 Bcl-2 expression was associated with significantly shorter survival (P < 0.05) and correlated with clinical stages and lymph node metastasis (P < 0.05 and P < 0.05, respectively). CONCLUSIONS: Loss of pSer70 Bcl-2 expression is closely linked to biological aggressiveness in colorectal tumors and represents a statistically significant molecular index for prognosis of patients with these tumors.

DOI： 10.1158/1078-0432.CCR-05-0274

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING  

Murine gammaherpesvirus (MHV)-68-infected mice are well-known as models for Epstein-Barr virus (EBV)-related lymphoproliferative diseases. MHV-72 may be a relative of MHV-68, but any genetic comparison between the two (except for the M7 gene) has never been reported. The genetic compositions of MHV-72 and MHV-68 were compared and the pathology of MHV-72 infection studied in CB-17 severe combined immunodeficiency (scid/scid; SCID) and CB17 wild-type (CB17+/+) mice. The MHV-72 DNA sequence was almost identical to MHV-68 except for approximately 7000 bp corresponding to the MHV-68 M1-M3 genes. Twenty-seven of 30 MHV-72-infected SCID mice (90%) died from generalized infection with intranuclear viral inclusions for approximately 1 month, while MHV-72-infected CB17+/+ mice recovered from acute infection. Long observation and pathological study of 68 MHV-72-infected mice for up to 24 months revealed that the survival rate (29.4%) and survival time (21.3 months) of MHV-72-infected CB17+/+ mice were significantly lower (P = 0.0127) and shorter (P = 0.0065) than those of the controls (61.1% and 22.9 months), respectively. The malignancy development rate (60.3%) of the infected CB17+/+ mice was also significantly higher (P = 0.004) than those of the controls (22.2%). However, no MHV-72 DNA was detected in the tumors of infected mice. MHV-72 may have some tumor-promoting effects but the tumorigenesis in infected CB17+/+ mice is different from EBV-associated tumors.

DOI： 10.1111/j.1440-1827.2005.01869.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

We investigated immune property of a myoid cell line, established from Fisher rat thymus. Immunization of syngeneic rats with the myoid cells induced anti-rat acetylcholine receptor (AChR). Implantation of them into the thymus failed to induce typical thymic pathology of human myasthenia gravis (MG) or anti-AChR responses. We also demonstrated that the myoid cells were able to present exogenous antigens to T cells and induce antigen-specific T cell proliferation. These results suggest that myoid cells have the potential antigenicity to induce anti-AChR and the functions of antigen-presenting cells, but their expansion in the thymus may not directly cause MG. (C) 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jneuroim.2004.01.022

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Epstein-Barr virus (EBV)-related herpesvirus (Si-IIA-EBV) was serially transmitted for 3 passages from rabbit to rabbit of the opposite sex by blood transfusion, which subsequently induced virus-associated rabbit lymphomas. The virus could be transmitted by transfusion with 15-20 ml of whole blood (7/7) or irradiated blood (1/6) from the EBV-related virus-infected rabbits, but there was no transmission with transfusion of cell-free plasma (0/6) from the infected rabbits. Passive anti-EBV-VCA IgG (x 20 similar to x 10) titers decreased during the first 1 - 2 weeks in the transfused rabbits. The virus-transmitted rabbits showed a gradual increase in antibody titers ranging from peak titers of X 640 to x 2560 after 3 weeks of transfusion. The recipient origin of malignant lymphoma that developed in the first rabbit transfused by infected blood was confirmed by chromosomal analysis. This rabbit model thus shows that EBV-related herpesvirus is serially transmissible by blood transfusion and that transmission can not be completely prevented by irradiation of blood, but removal of blood cells is the best way to prevent transmission of EBV-related virus. Therefore, this animal model provides a convenient in vivo system for studies of the prevention and therapy of transfusion -related transmission of EBV and EBV-associated lymphoproliferative diseases in immunocompromised human beings.

DOI： 10.18926/AMO/32097

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

Mantle cell lymphoma (MCL) is a CD5(+) nonHodgkin's B-cell lymphoma characterized by the infiltration of intermediate sized B-cells into the mantle zones. Interaction between CD40L and CD40 is important for B cell proliferation and differentiation. CD40L stimulation can induce both growth arrest and proliferation of B cell lines according to their differentiation state. Previous reports examining the effect of stimulation via the CD40 cascade on ex vivo MCL cells have provided conflicting results. In this study, two MCL lines, SP49 and SP53, were examined for response to CD40L and/or IL-10. Co-cultivation with CD40L-erpressing mouse L cells reduced the BrdU incorporation of SP49 and SP53 cells by half to one-third while BrdU incorporation of control cell lines, including Ramos, BJAB and BALL-1, was not affected or increased. Anti-CD40L antibody blocked the CD40L inhibition of SP49 cell proliferation in a dose-dependent manner in the range from 0 to 20 ng/ml. IL-10 did not affect AICL cell proliferation in the presence or absence of CD40L-expressing cells, while Ramos proliferation was promoted by CD40L and IL-10. These results suggested the possibility that CD40L may also inhibit MCL proliferation in vivo.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Previously we showed reduced protein and mRNA expression of the SHP1 gene in lymphoma/leukemia cell lines and patient specimens by Northern blot, RT-PCR, Western blot, and immunohistochemical analyses. In this study, aberrant methylation in the SHP1 gene promoter was detected in many B-cell leukemia/lymphoma cell lines as well as in patient specimens, including diffuse large B-cell lymphoma (methylation frequency 93%), MALT lymphoma (82%), mantle cell lymphoma (75%), plasmacytoma (100%) and follicular lymphoma (96%) by methylation-specific PCR, bisulfite sequencing, and restriction enzyme-mediated PCR analyses. The methylation frequency was significantly higher in high-grade MALT lymphoma cases (100%) than in low-grade MALT lymphoma cases (70%), which correlated well with the frequency of no expression of SHP1 protein in high-grade (80%) and low-grade MALT lymphoma (54%). It suggests that the SHP1 gene silencing with aberrant CpG methylation relates to the lymphoma progression. SHP1 protein expression was recovered in B-cell lines after the treatment of the demethylating reagent: 5-aza-2'-deoxycytidine. Transfection of the intact SHP1 gene to the hematopoietic cultured cells, which show no expression of the SHP1 gene, induced growth inhibition, indicating that gene silencing of the SHP1 gene by aberrant methylation plays an important role to get the growth advantage of the malignant lymphoma/leukemia cells. The extraordinarily high frequency (75 to 100%) of CpG methylation of the SHP1 gene in B-cell lymphoma/leukemia patient specimens indicates that the SHP1 gene silencing is one of the critical events to the onset of malignant lymphomas/leukemias as well as important implications for the diagnostic or prognostic markers and the target of gene therapy. These data support the possibility that the SHP1 gene is one of the tumor suppressor genes.

DOI： 10.1097/01.LAB.0000106503.65258.2B

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Using cDNA expression array and tissue microarray, we comprehensively and systematically analyzed the expression profile to investigate the lymphomagenesis. We detected the significant decrease of hematopoietic cell specific protein-tyrosine phosphatase SHP1 gene expression in various malignant lymphomas and leukemias. High-frequent silencing of the SHP1 gene by promoter methylation was detected in various kinds of leukemias and lymphomas as well as in many hematopoietic cell lines. The promoter methylation of the SHP1 gene was significantly correlated with the clinical stage. Loss of heterozygosity with microsatellite markers around the SHP1 gene was detected in 79% of informative ALL cases. These results suggest that loss of functional SHP1 is closely associated with the pathogenesis of leukemias/lymphomas.

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Language：Japanese   Publisher：日本臨床社  

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Other Link： http://search.jamas.or.jp/link/ui/2004059364

Language：English   Publishing type：Research paper (scientific journal)   Publisher：F HERNANDEZ  

Epstein-Barr virus-associated hemophagocytic syndrome (EBV-AHS), which is often associated with fatal infectious mononucleosis or T-cell lymphoproliferative diseases (LPD), is a distinct disease characterized by high mortality. Treatment of patients with EBV-AHS has proved challenging. To develop some therapeutic interventions for EBV-AHS, we examined the effectiveness of an antiviral agent (vidarabine) or chemotherapy (CHOP), using a rabbit model for EBV-AHS.
Fourteen untreated rabbits were inoculated intravenously with cell-free virions of the EBV-Iike virus Herpesvirus papio (HVP). All of the rabbits died of HVP-associated (LPD) and hemophagocytic syndrome (HPS) between 21 and 31 days after inoculation. Furthermore, three HVP-infected rabbits treated with vidarabine died between days 23 and 28 after inoculation, and their clinicopathological features were no different from those of untreated rabbits, indicating that this drug is not effective at all to treat HVP-induced rabbit LPD and HPS.
Three of the infected rabbits that were treated with one course, with an incomplete set of three courses, or with three full courses of CHOP treatment died of HVP-induced LPD and HPS with a bleeding tendency and/or with opportunistic infections. They died on the 26th, 62nd and 105th day after virus inoculation, respectively. CHOP treatment transiently suppressed the HVP-induced LPD and contributed to the prolonged survival time of two infected rabbits. However, it did not remove all of the HVP-infected cells from the infected rabbits, and residual HVP-infected lymphocytes caused recurrences of rabbit LPD and HPS. The most interesting finding of this experiment was observed in the infected rabbit with the longest survival time of 105 days: HVP-negative lymphomas surrounded by HVP-induced LPD developed in the larynx and ileum of this rabbit, causing an obstruction of the lumen. We concluded that these were not secondary lymphomas caused by CHOP treatment, because no suspicious lesions were detected in three uninfected rabbits that were treated with three courses of CHOP for 120 days. It is therefore necessary to clarify the mechanism by which HVP-negative lymphomas associated with HVP-induced LPD can develop.
Our data from therapeutic trials using EBV-AHS animal models indicate that vidarabine is not effective as an agent to treat HVP-infected rabbits, and even the cytotoxic chemotherapy of CHOP is not sufficient to cure the HVP-infected rabbits or to prolong the survival time of infected rabbits. Further studies will therefore be required to develop better therapies to treat EBV-AHS.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC INVESTIGATIVE PATHOLOGY, INC  

Epstein-Barr virus-associated hemophagocytic syndrome (EBV-AHS) is often associated with fatal infectious mononucleosis or T-cell lymphoproliferative diseases (LPD). To elucidate the true nature of fatal LPD observed in Herpesvirus papio (HVP)-induced rabbit hemophagocytosis, reactive or neoplastic, we analyzed sequential development of HVP-induced rabbit LPD and their cell lines. All of the seven Japanese White rabbits inoculated intravenously with HVP died of fatal LPD 18 to 27 days after inoculation. LPD was also accompanied by hemophagocytic syndrome (HPS) in five of these seven rabbits. Sequential autopsy revealed splenomegaly and swollen lymph nodes, often accompanied by bleeding, which developed in the last week. Atypical lymphoid cells infiltrated many organs with a "starry sky" pattern, frequently involving the spleen, lymph nodes, and liver. HVP-small RNA-1 expression in these lymphoid cells was clearly demonstrated by a newly developed in situ hybridization (ISH) system. HVP-ISH of immunomagnetically purified lymphoid cells from spleen or lymph nodes revealed HVP-EBER1+ cells in each CD4+, CD8+, or CD79a+ fraction. Hemophagocytic histiocytosis was observed in the lymph nodes, spleen, bone marrow, and thymus. HVP-DNA was detected in the tissues and peripheral blood from the infected rabbits by PCR or Southern blot analysis. Clonality analysis of HVP-induced LPD by Southern blotting with TCR gene probe revealed polyclonal bands, suggesting polyclonal proliferation. Six IL-2-dependent rabbit T-cell lines were established from transplanted scid mouse tumors from LPD. These showed latency type I/II HVP infection and had normal karyotypes except for one line, and three of them showed tumorigenicity in nude mice. These data suggest that HVP-induced fatal LPD in rabbits is reactive polyclonally in nature.

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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High-frequent silencing of hematopoietic cell-specific protein-tyrosine phosphatase SHP1 gene by promoter methylation was detected in various kinds of leukemias and lymphomas, as well as in many hematopoietic cell lines, which is supported by our previous observation of strong decrease of SHP1 mRNA and protein. The promoter methylation of the SHP1 gene was clearly correlated with the clinical stage. Loss of heterozygosity with microsatellite markers near the SHP1 gene was shown in 79% of informative acute lymphoblastic leukemia cases. These results suggest that functional loss of SHP1 is associated with the pathogenesis of leukemias/lymphomas.

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Language：English   Publisher：The Japanese Society for Lymphoreticular Tissue Research  

A molecular chaperonin in mammals, heat shock protein 60 (HSP60) is constitutively expressed in the mitochondria at a low level and is rapidly up-regulated under stress. However, the role of HSP60 in the lymphoid tissues has not been well clarified. In the present study, expression of HSP60 was examined by flow cytometry and immunohistochemistry in normal peripheral blood mononuclear cells, reactive lymphoid tissues, and malignant lymphomas. HSP60 was found to be present constitutively at low levels in a fraction of resting T cells and most monocytes. The blastic change upon mitogen stimulation induced HSP60 at much higher levels in more T, B and NK cells. In normal lymphoid tissues, HSP60 was expressed preferentially in the cytoplasm of large-sized lymphoid cells and macrophages in the germinal centers and the interfollicular area.<br>In non-Hodgkin lymphomas strong expression of HSP60 was detected in most cases of diffuse large B-cell lymphoma, follicular lymphoma, and grade 3 and NK/T cell lymphoma. No immunostaining was observed in low grade B-cell lymphomas, including follicular lymphoma, grade 1 and B-lymphoblastic lymphomas. HSP60 immunoreactivity was variable in T-cell lymphomas. Intense expression of HSP60 was observed in Reed-Sternberg cells in all cases of Hodgkin lymphoma.

DOI： 10.3960/jslrt.42.25

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Language：English   Publisher：OKAYAMA UNIV MED SCHOOL  

The structure of the human genome is almost completely elucidated and the life sciences will now aim for a general and integrated study of gene expressions and the functional elucidation of proteins. In such a study, various new techniques have been developed, and DNA microarray technology is the most representative one. As for the DNA microarray techniques, several thousands to tens of thousands of gene segments are immobilized on a glass slide at high density, and cDNA probes prepared from specific cells or tissues are hybridized on the slides from which gene expression profiles are obtained at one sweep in a short time. The present development of this technique and its possible application to medicine-related fields are described.

DOI： 10.18926/AMO/32002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC INVESTIGATIVE PATHOLOGY, INC  

To investigate the lymphomagenesis of NK/T lymphoma, we comprehensively and systematically analyzed the expression pattern of the human NK/T cell line (NK-YS) genome by cDNA expression array and tissue microarray. We detected significant changes in the gene expression of NK-YS cell line: an increase in 18 and a decrease in 20 genes compared to normal NK cells or peripheral blood mononuclear cells. Among these genes, we found a strong decrease in hematopoietic cell specific protein-tyrosine-phosphatase SHPTP1 (SHP1) mRNA by cDNA expression array and reverse transcriptase-polymerase chain reaction. Further analysis with standard immunohistochemistry and tissue microarray, which used 207 paraffin-embedded specimens of various kinds of malignant lymphomas, showed that 100% of NK/T lymphoma specimens and more than 95% of various types of malignant lymphoma. were negative for SHP1 protein expression. On the other hand, SHP1 protein was strongly expressed in the mantle zone and interfollicular zone lymphocytes in reactive lymphoid hyperplasia specimens. In addition, various kinds of hematopoietic cell lines, particularly the highly aggressive lymphoma/leukemia lines, lacked SHP1 expression in vitro, suggesting that loss of SHP1 expression may be related to not only malignant transformation, but also tumor cell aggressiveness. SHP1 expression could not be induced in either of two NK/T cell fines by phorbol ester, suggesting that genetic impairment or modification with methylation of SHP1 DNA could be one of the critical events in the pathogenesis of NK/T lymphoma. This evidence strongly suggests that loss of SHP1 gene expression plays an important role in multistep tumorigenesis, possibly as an anti-oncogene in the wide range of lymphomas/leukemias as well as NK/T lymphomas.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Expression of adhesion molecule in low-grade B-cell mucosa-associated lymphoid tissue (MALT) lymphoma of the gastrointestinal tract has been reported in recent years, but these reports have primarily focused on low-grade gastrointestinal MALT lymphoma. In this study, we examined the lymphocytic homing receptor alpha4 beta7 integrin, L-selectin, and VLA-4 and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in low-grade lymphoma of the gastrointestinal tract and other organs such as the ocular adnexa and thyroid. We also observed changes in the expression pattern associated with high-grade transformation. Neoplastic cells in the gastrointestinal low-grade lymphoma and the low-grade component of high-grade MALT lymphoma were found to be alpha4 beta7 integrin(+), L-selectin(+), whereas the gastrointestinal high-grade component and diffuse large B-cell lymphoma were found to be alpha4 beta7 integrin(-), L-selectin(-). High endothelial venules in the gastric MALT lymphomas expressed MAdCAM-1. In the ocular adnexa. low-grade MALT lymphoma, most cases were alpha4 beta7 integrin(-), L-selectin(+); and in the thyroid, most cases of both low- and high-grade MALT lymphoma were alpha4 beta7 integrin-, L-selectin(-). These findings show that alpha4 beta7 integrin and L-selectin may play an important role in the lymphocyte homing of gastrointestinal low-grade MALT lymphoma and in the loss of alpha4 beta7 integrin expression throughout the course of high-grade progression.

DOI： 10.1038/modpathol.3880393

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC INVESTIGATIVE PATHOLOGY, INC  

Interdigitating dendritic cells (IDC) of the human mesenteric lymph nodes (LN) were examined by two-color immunofluorescent microscopy and flow cytometry to clarify their exact localization, immunophenotype, and relationships with T and B cells. IDC were identified as HLA-DRbright large dendriform cells of the T cell areas co-expressing CD40, CD54 (ICAM-1), CD80 (B7/B7-1), CD83, and CD86 (B70/B7-2). The majority of IDC directly attached to a few IgD+ naive B cells as well as to numerous CD4+ T cells. When LN cells were singly suspended and briefly incubated in vitro, IDC formed clusters with IgD+ IgM+ naive B cells, but not with IgA+ or IgG+ B cells. When suspended LN cells were cultured, clustered B cells disappeared within 7 days, and on prolonged culture, some IDC developed into extensively dendriform cells forming stable complexes with several or sometimes numerous CD4+ IL-2R+ CD40L+ activated T cells. These findings indicate that resting naive B cells actually interact with IDC directly in T cell areas of human secondary lymphoid tissues. IDC have a non-antigen (Ag)-specific, strong affinity for resting naive B cells, but this affinity is transient and IDC cannot form stable complexes with B cells, although they can form stable complexes with activated T cells. It is suggested that the stable IDC/Ag-activated T cell complexes make it possible to capture and to stimulate rare Ag-specific resting naive B cells with high efficiency.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC INVESTIGATIVE PATHOLOGY, INC  

Epstein-Barr virus-associated hemophagocytic syndrome (EBV-AHS) Is often associated with fatal infectious mononucleosis. However, the animal model for EBV-AHS has not been developed. We reported the first animal model for EBV-AHS using rabbits infected with EBV-related herpesvirus of baboon (HVP), Eleven of 13 (85%) rabbits inoculated intravenously with HVP-producing cells developed fatal lymphoproliferative disorders (LPD) between 22 and 105 days after Inoculation. LPD was also accompanied by hemophagocytic syndrome (HPS) in nine of these 11 rabbits, The peroral spray of cell-free HVP induced the virus infection with increased anti-EBV-viral capsid antigen-IgG titers in three of five rabbits, and two of these three infected rabbits died of LPD with HPS, Autopsy revealed hepatosplenomegaly and swollen lymph nodes. Atypical lymphoid T cells expressing EBV-encoded small RNA-I infiltrated diffusely in many organs, frequently involving the lymph nodes, spleen, and liver. Hemophagocytic histiocytosis was observed in the lymph nodes, spleen, bone marrow, and thymus, HVP-DNA was detected in the tissues and peripheral blood from the infected rabbits by polymerase chain reaction or Southern blot analysis. Re-verse transcriptase-polymerase chain reaction revealed both HVP-EBNA1 and HVP-EBNA2 transcripts, suggesting latency type Ri infection. These data indicate that the high rate of rabbit LPD with HPS induction is caused by HVP, This system is useful for studying the pathogenesis, prevention, and treatment of human EBV-AHS.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER VERLAG  

A thymus-derived myoid precursor cell line (STI), which differentiates to myoid cells in the growth arrest condition, was established by the cocultivation of F344 rat thymic cells with human T-lymphotropic virus type-I (HTLV-I)-producing human lymphoid cells. No integration of HTLV-I was detected in ST1 cells by Southern blot hybridization. III a differentiation culture condition such as confluent culture or serum starvation, STI cells began to fuse, creating multinuclear giant cells, with the induced expression of MyoD1 and various muscle-specific antigens, including a-sarcomeric actin, skeletal muscle myosin, myoglobin, desmin, and acetylcholine receptor. Ultrastructural investigation revealed that differentiated ST1B cells created aggregates of thick and thin filaments with Z-band-like composition, then formed sarcomeric structures and tubular honeycomb arrays. Finally, these cells spontaneously contracted with a frequency of 0.5-2.0 Hz and synchronized with adjoining cells. Transplantation of ST1B cells into nude mice produced a small tumor nodule, showing clear differentiation to skeletal muscle cells. ST1B cells did not indicate any colony-forming activities in soft agar, demonstrating that ST1B cells retain some of the physiologically normal phenotypes. This rare cell line is promising for use in various physiological and pathological investigations including functional research of thymic myoid cells and the pathological role in autoimmune diseases, as well as animal model experiments of cell therapy related to muscular degenerative disorders or regeneration of injured muscles.

DOI： 10.1007/s004410050053

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Objectives:The Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA-1) is an important protein for immortalization and tumorigenesis of infected cells. EBNA-1 gene variants may play a role in tumorigenesis. We determined the nucleotide and amino acid (aa) sequences of EBNA-1 in EBV-related herpesviruses from cynomolgus monkeys (cynomolgus-EBV) which induced malignant lymphomas in its natural host and in rabbits, and compared them with sequences of EBV and other lymphocryptoviruses (LCVs). Methods: Polymerase chain reaction and direct sequencing methods were performed using extracted DNA from cynomolgus-EBV-infected cell lines. Results: The amino acid sequences of cynomolgus-EBV EBNA-1 from two cell lines (SI-IIA: 588 aa; Ts-BG: 619 aa) which are antigenically cross-reactive to human EBV EBNA-1 showed homology with human EBV (SI-IIA: 53%; Ts-BG: 58%) and other LCVs from baboons (54 and 52%) and rhesus monkeys (60 and 58%), especially in the C-terminal unique domain. Homology of the EBNA-1 sequence between SI-IIA and Ts-BG was 92%. The sequence difference between EBV and the related LCVs was manifested mainly in the length of the internal repeat 3-corresponding region, which contains serine in the glycine/alanine repeat region of nonhuman LCVs. Conclusion: Sequence variation of cynomolgus-EBV EBNA-1 from different cell lines was observed. However, their sequences show a relatively high homology with human EBV and share the common features of EBNA-1 of EBV and other LCVs. Copyright (C) 2000 S. Karger AG, Basel.

DOI： 10.1159/000025031

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Lippincott Williams and Wilkins  

Almost all nasopharyngeal carcinomas (NPCs) are infected by Epstein-Barr virus (EBV), but most ex vivo NPC cells lose EBV genomes during passages. In this study, an EBV-negative NPC cell line, TW03, established from EBV- carrying NPC was reinfected with EBV by cocultivation with irradiated Akata cells carrying recombinant EBV containing a neomycin-resistant gene. The reinfected EBV (+) TW03 cells expressed EBERs and EBNA1, but not EBNA2, lytic proteins (ZEBRA and EA-D), or LMP1. They had an epithelial appearance similar to that of EBV (-) TW03 cells. The doubling times of EBV (+) and EBV () TW03 cells were almost identical. However, the EBV (+) TW03 cells formed larger colonies with ragged contours in anchorage-independent cultures. An in vitro invasion assay showed that EBV (+) TW03 cells had a higher invasive activity than EBV () TW03 cells (p &lt
0.01). Both EBV () and EBV (+) TW03 cells formed poorly differentiated squamous cell carcinomas in SCID and nude mice. EBV (+) TW03 cells showed a higher tumorigenicity to nude mice (12 of 13) than EBV (- ) TW03 cells (1 of 9) (p &lt
0.001). In the severe combined immunodeficiency (SCID) tumors of EBV (+) TW03 cells, not all of the tumor cells were EBER-1 positive. EBER-1 was more frequently detected in the peripheral regions and daughter nodules of the tumors than in the central areas. The microdissection polymerase chain reaction showed that the EBER-1 -negative TW03 cells in the EBV (+) TW03 SCID tumors lost EBV genomes. EBER-1-negative cells showed as high a rate of Ki-67 positivity as EBER-1-positive cells, indicating that the former were proliferating rather than dead or dying. In horny pearls, keratinizing cells were ZEBRA-positive and EBER-negative. Loss of EBV genomes was not associated with squamous differentiation. These data indicated that reinfection of EBV promotes the tumorigenicity of EBV (-) TW03 cells by enhancing the invading activity.

DOI： 10.1038/labinvest.3780035

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Malignant lymphoma (ML) induction in rabbits by Epstein-Barr virus (EBV)-related herpesvirus of cynomolgus (Cyno-EBV) is reported. Twenty-seven of 30 (90%) rabbits inoculated intravenously with Cyno-EBV-producing simian (cynomolgus) lymphocyte cell line (Ts-B6) cells developed ML between 45 and 115 days after inoculation. The peroral inoculation of Ts-B6 cells induced ML in only 2 of 10 (20%) rabbits (75 to 85 days). Five of 6 (83%) rabbits injected with cell-free pellets from Ts-B6 cultures also developed ML (27 to 122 days). Antibody response to the viral capsid antigen of EBV was also detected in sera from rabbits inoculated with Ts-B6. ML of the large cell or mixed type infiltrated diffusely in many organs, frequently involving the spleen, liver, kidneys, heart, and less frequently the lungs, lymph nodes, brain, eyes, gastrointestinal tract, thymus, and bone marrow. A chromosomal analysis of five lymphoma cell lines established from tumor-bearing rabbits revealed the rabbit karyotype. Three of these cell lines showed the chromosomal abnormalities with 12q- or t (7p+:12q-). EBV-encoded small RNA-1 and EBV-associated nuclear antigen 1 were expressed in Ts-B6 cells, the tumor tissues, and all rabbit cell lines by in situ hybridization and by immunofluorescence tests, respectively. EBV DNA was also detected in Ts-B6 cells and rabbit lymphoma cell lines by polymerase chain reaction and Southern blot analysis. The Southern blots of EBV termini revealed oligoclonal bands in the Cyno-EBV-induced rabbit lymphomas. No lymphoma was induced by the inoculation of B95-8 (EBV-producing cells) or peripheral leukocytes from normal cynomolgus (controls). These data suggest that the high rate of lymphoma induction in rabbits may be caused not by human EBV (B95-8) but by Cyno-EBV from Ts-B6 cells. A sequence analysis of the IR1 (BamHIW) region of Cyno-EBV revealed that this region is quite similar to that of herpesvirus Macaca fascicularis 1,which is a causative agent for a monkey model of AIDS-retated lymphomas. The present rabbit model of lymphoma with specific chromosomal abnormalities is very useful to clarify the role of EBV in human EBV-associated lymphoma and provides a means for studying prophylactic and therapeutic regimens.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Publishing Group  

Interferon-alpha treatment induces complete cytogenetic remission in 25% of Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) patients. These remissions are durable unlike remissions induced with other therapies and yet residual leukemia is detectable in most of these patients. Total peripheral blood mononuclear cells (PBMCs) from CML patients in long-term remission following interferon treatment exhibited significantly higher proliferative responses (four- to 15-fold over background) than normals directed against P210 BCR-ABL in extracts of transfected monkey fibroblast cells. Surprisingly, similar enhanced levels of specific proliferative responses were observed with extracts from cells expressing Bcr and/or Abl proteins. In contrast, extracts from vector only or v-Mos-expressing cells had background level responses. Control monkey fibroblast cells lacking BCR-ABL expression failed to induce proliferation over background levels. Normal individuals had no significant responses to Bcr/Abl extracts. On the other hand, peripheral blood mononuclear cells from allogeneic bone marrow transplant CML patients had proliferative responses to cell extracts independent of Bcr-Abl. These data indicate that patients in remission due to alpha-interferon treatment have significantly higher levels of specific cellular immunoreactivity against Bcr/Abl sequences than normal controls, which could play a role in maintaining cytogenetic remission in Ph-positive CML patients.

DOI： 10.1038/sj.leu.2400919

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Cancer Association  

To investigate whether the lymphocyte homing receptors, adhesion molecules regulating normal lymphocyte traffic, influence the dissemination of lymphoma cells, 24 lymphoma/leukemia cell lines were inoculated into SCID mice subcutaneously, and the correlation between the expression of the adhesion molecules and the metastatic potential of the cell lines was examined. Among the six adhesion molecules examined (LFA-1, ICAM-1, CLA, VLA-4, L-selectin and CD44), L-selectin increased the incidence of lymph node metastasis, and CD44 expression was related to both lymph node and organ (hematogenous) metastasis. A monoclonal antibody to the standard form of CD44 (CD44s), Hermes-3, inhibited the local growth and remote metastasis of CD44+ cell lines. Thus, it is concluded that at least CD44s expression is important in both lymphatic and hematogenous metastasis.

DOI： 10.1111/j.1349-7006.1996.tb03112.x

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Many proteins containing domains of a cysteine-rich repeated motif, such as epidermal growth factor (EGF), have been reported. Here we report strong similarity between the amino acid sequence of a plant toxin-i.e., purothionin and its homologues-and with those of a domain found in mammalian pore-forming cytoplasmic proteins: components of complement and perforin of cytotoxic T- lymphocytes or natural killer-like cytotoxic cells. These similar sequences were found to be identical to the so-called EGF-like cysteine-rich repeated motif itself. Electronmicroscopic observations indicated that, like complement and perforin, purothionin forms pores in the cytoplasmic membrane of target cells, resulting in their death within a few hours. On the basis of these sequence comparisons and physiological functions, we propose a scheme for the evolution of proteins containing modules of the cysteine-rich repeat motif.

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The effects of human interferon (IFN)‐α, ‐β, and ‐γ on the immortalization of human and rabbit lymphocytes by human T‐lymphotropic virus type‐l (HTLV‐I) have been investigated. The immortalization of human peripheral‐blood lymphocytes co‐cultured with lethally X‐ray‐irradiated HTLV‐l‐producer cells, MT‐2, was blocked in the presence of more than 40 u/ml human recombinant IFN‐α or more than 200 u/ml human natural type IFN‐fi. However, rhlFN‐γ did not block immortalization by HTLV‐I even at higher doses. On the other hand, the presence of high doses of hlFN‐α, ‐β, or ‐γ did not exhibit any biological effect on the immortalization of rabbit peripheral‐blood lymphocytes co‐cultured with lethally X‐ray‐irradiated MT‐2 cells. Integration of the full length of HTLV‐I genome was detected in every transformant by Southern blot analysis. All cell lines established were CD4+/CD8÷ T‐lymphocytes, except for one cell line of CD4+/CD8+. Morphologically intact HTLV‐I production was observed by electron microscopy in these cells. Our results indicate that HTLV‐I released under the strongly suppressed condition in the presence of IFNs remains active and able to immortalize T lymphocytes. It is also suggested that immortalization of human T lymphocytes by HTLV‐I can be inhibited by the antiviral state induced by the treatment with low doses of hlFN‐α and ‐β, whereas immortalization of rabbit T lymphocytes is not inhibited because of the species specificity of hlFNs. Copyright © 1992 Wiley‐Liss, Inc., A Wiley Company

DOI： 10.1002/ijc.2910510614

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Single cilium formation was studied in two human hematopoietic cell lines, KCL-22 and MT-2. KCL-22 established from a patient with chronic myelogenous leukemia in blastic crisis, and MT-2, a human cord T cell line carrying human T-lymphotropic virus type I, were transplanted into hamsters. Ciliogenesis was observed in both cell lines, only after transplantation into hamsters.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER VERLAG  

A newly established human osteosarcoma cell line, HS-Os-1, from an osteoblastic tumor arising in the left humerus of an 11-year-old girl was morphologically characterized in vitro and in vivo. HS-Os-1 cells in a monolayer have been maintained for more than 2 years since the initial cultivation, and were round or polygonal in shape with marked pleomorphism. Their cytoplasm was strongly positive for specific markers of osteoblasts, such as alkaline phosphatase and osteocalcin. Tumors induced in nude mice by HS-Os-1 cell inoculation at passage 12 or 23 revealed typical histological features of osteoblastic osteosarcoma, similar to those observed in the original tumor, producing prominent osteoid matrix with calcification. Ultrastructurally, HS-Os-1 cells in vitro and tumor cells in vivo showed similar well-developed, markedly dilated rough endoplasmic reticulum, polysomes and microfilaments in their cytoplasm. Additionally, many collagen fibers associated with deposition of electron-dense material were detected in the stroma featuring osteoid matrix. Thus, the HS-Os-1 cell line was shown to exhibit its osteoblastic nature in vitro and in vivo, and therefore might become an extremely useful tool for various pathomorphological investigations on human osteosarcomas.

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Transformed Fisher rat fibroblast cell lines by Abelson murine leukemia virus frequently revert to the normal phenotype in usual culture conditions. Molecular Biological analysis of thre revertant clones isolated from the transformants showed that their morphological reversions were due to inactivation of the v‐abl oncogene at multiple steps including transcription, translation or v‐abl protein kinase activity itself without any change in structural gene expression of helper virus. These findings suggest the existence of a specific mechanism(s) for elimination of the v‐abl oncogene by segregation, mutation, or gene rearrangement in these cells. Copyright © 1990 Wiley‐Liss, Inc.

DOI： 10.1002/jcp.1041450306

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Language：English   Publisher：Okayama University Medical School  

DOI： 10.18926/AMO/30886

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Paramecium cells adapted to 2 mM K+ were voltage clamped and transient inward currents induced by step-depolarizations were studied. When the external K+ concentration was increased to 8 mM, the inward current was largely suppressed. Similar suppression of the inward current was induced by positive shifts of the holding potential above the resting level. The suppression of inward current is, therefore, primarily caused by depolarizing changes in the membrane potential. During adaptation to 8 mM K+, the inward current recovered to about 70% of that in the cells adapted to 2 mM K+, the resting membrane repolarized, and the steady state inactivation of the inward current was shifted to a more positive level than the cells adapted to 2 mM K+. When mutant cells which lack depolarization-sensitive Ca-current were adapted to 8 mM K+, a step-depolarization induced a fast activation of outward current, which would subtract from the inward current in the wild-type cells, suggesting that the transient inward current of cells adapted to 8 mM K+ is partially reduced by the fast activation of outward current. © 1989, Japan Society for Cell Biology. All rights reserved.

DOI： 10.1247/csf.14.209

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Co‐cultivation of spleen cells of Syrian golden hamsters with lethally irradiated MT‐2 cells harboring human T‐cell leukemia virus type I (HTLV‐I) resulted in the establishment of lymphoid cell lines, HCT‐1 and HCT‐2, which exhibited the normal karyotype of golden hamsters. Cells of both the HCT‐1 and HCT‐2 lines lacked surface immunoglobulins and reacted with a monoclonal antibody (MAb) specific for hamster T cells. Some were positive for OKIal. None of them expressed HTLV structural antigens (p19 and p24) or virus particles, but they contained HTLV‐1 proviral DNA monoclonally. By immunochemical analysis of the labelled cell antigens, sera from adult T‐cell leukemia (ATL) patients reacted with the two polypeptides, p37 and p40, which may not be viral structural proteins and still remain to be characterized. HCT‐1 and HCT‐2 cells were transplantable into newborn hamsters, pre‐treated with anti‐hamster thymocyte serum and non‐treated, respectively, producing diffuse malignant lymphoma. These findings indicated that HTLV‐1 not only immortalized but also transformed hamster T cells non‐productively. Copyright © 1986 Wiley‐Liss, Inc., A Wiley Company

DOI： 10.1002/ijc.2910370520

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DOI： 10.20772/cancersci1985.76.2_86

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DOI： 10.20772/cancersci1985.76.2_86

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Some characteristics of T cell growth factors derived from adult T cell leukemia virus (ATLV)-transformed cell lines, MT 1 and MT 2 were analyzed. MT 1 cells release significant interleukin 2 (IL 2) activity into the culture medium, which showed the same elution pattern of gel filtration and isoelectric focusing of IL 2 from lectin-stimulated normal human lymphocytes. This activity was also detected in the cell extract of MT 1. In contrast, MT 2 cell line did not produce IL 2 activity, but non-IL 2 type growth factor was observed. The significance of these factors from MT cell lines is discussed from the viewpoint of 'autokine' in ATLV-transformed cells. ALTV-transformed cell T cell growth factor. © 1984.

DOI： 10.1016/0014-5793(84)81283-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC CELL BIOLOGY  

DOI： 10.1247/csf.8.77

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Language：Japanese   Publisher：(一社)日本リンパ網内系学会  

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：English   Publisher：日本癌学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2012-1034

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM10-LB-246

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SPANDIDOS PUBL LTD  

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Language：English   Publisher：OKAYAMA UNIV MED SCHOOL  

It has been reported that Epstein-Barr virus (EBV) resides in resting B cells in vivo. However, an ideal in vitro system for studying EBV latent infection in vivo has not yet been established. In this study, a mantle cell lymphoma line, SP53, was successfully infected with a recombinant EBV containing a neomycin-resistant gene. The EBV-carrying SP53 cells were obtained by selection using G418. They expressed EBER-1, EBNAs, and LMP1; this expression pattern of the EBV genes was similar to that in a lymphoblastoid cell line (LCL). However, proliferation assay showed that the EBV-carrying SP53 cells have a doubling time of 73 h, compared with 57 h of SP53 cells. Transplantation of 10(8) SP53 cells to nude mice formed tumors in 4 of 10 mice inoculated, but the EBV-carring SP53 cells did not. Unexpectedly, EBV infection reduced the proliferation and tumorigenicity of SP53 cells. However, the EBV-carrying SP53 cells showed higher resistance to apoptosis induced by serum starvation than did the SP53 cells. The inhibition of proliferation and the resistance to apoptosis induced in SP53 cells by EBV infection indicate that this cell line might to some extent provide a model of in vivo EBV reservoir cells.

DOI： 10.18926/AMO/32293

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