Naoki Wada

Osaka University, Suita, Osaka-fu, Japan

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Publications (22)48.84 Total impact

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    ABSTRACT: Cancer cells with tumorigenic potential are limited to a small population known as cancer-initiating cells (CICs). To date, CICs have not been identified in non-Hodgkin's lymphomas. Here, we investigated a candidate of CICs of an indolent non-Hodgkin's lymphoma, Waldenstrom macroglobulinemia (WM), using WM cell line MWCL-1. WM tumor expresses both B-cell and plasma cell markers, CD20 and CD138. When stained with anti-CD20 and anti-CD138 antibodies, MWCL-1 cells were classified into three subpopulations: CD20(-) CD138(-), CD20(+) CD138(-), and CD20(+) CD138(+). When cultured, CD20(-) CD138(-) cells yielded all three subpopulations, but CD20(+) cells did not yield CD20(-) CD138(-) cells. Higher reactive oxygen species (ROS) expelling and in vitro colony formation activities were detected in CD20(-) CD138(-) cells than in CD20(+) CD138(-) and CD20(+) CD138(+) cells. When cultured in the absence of serum or with anti-cancer drug, CD20(-) CD138(-) cells were resistant to apoptosis. In contrast, CD20(+) CD138(+) cells were vulnerable to apoptosis in the same condition. In fact, the immunohistochemical analysis with clinical samples revealed that tumor cells in apoptosis were CD138-positive. The production of all three subpopulations, the efficient ROS expelling and in vitro colony-forming activities, and the resistance to apoptosis suggested that the CD20(-) CD138(-) cell might be a candidate of CICs in WM.Laboratory Investigation advance online publication, 4 November 2013; doi:10.1038/labinvest.2013.129.
    Laboratory Investigation 11/2013; · 3.96 Impact Factor
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    ABSTRACT: Cancers consist of heterogeneous populations. Recently, it has been demonstrated that cells with tumorigenic potential are limited to a small population, called cancer-initiating cells (CICs). Aldehyde dehydrohenase 1 (ALDH1) is one of the markers of CICs. We previously reported that ALDH1-high cases of uterine endometrioid adenocarcinoma showed poor prognosis, and ALDH1-high population of endometrioid adenocarcinoma cell line was more tumorigenic, resistant to anti-cancer drugs, and invasive than ALDH1-low population. Here, the regulatory signaling for ALDH1 was examined. The inhibition of TGF- β signaling increased ALDH1-high population. Among TGF- β family members, Nodal expression and ALDH1 expression levels were mutually exclusive. Immunohistochemical analysis on clinical samples revealed Nodal-high tumor cells to be ALDH-low and vise versa, suggesting that Nodal may inhibit ALDH1 expression via stimulating TGF-β signaling in uterine endometrioid adenocarcinoma. In fact, the addition of Nodal to endometrioid adenocarcinoma cell line reduced ALDH1-high population. Although ALDH1 mRNA level was not affected, the amount of ALDH1 protein appeared to be reduce by Nodal through ubiquitine-proteasome pathway. The regulation of TGF-β signaling might be a novel therapeutic target of CICs in endometrioid adenocarcinoma.
    Biochemical and Biophysical Research Communications 10/2013; · 2.41 Impact Factor
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    ABSTRACT: Cancer-initiating cells (CICs) are a limited number of cells with tumorigenic activity. Few studies have been performed on CICs in malignant lymphoma. We recently demonstrated that a small number of FoxO3a-expressing cells possessed CIC-like potential in Hodgkin's lymphoma (HL) cell lines. In the present study, FoxO3a expression was examined immunohistochemically in 137 patients with malignant lymphoma. Among patients with HL, FoxO3a-positive tumor cells were detected in 11 of 11 with nodular sclerosis classical HL, 8 of 15 with mixed cellularity classical HL, 0 of 1 with lymphocyte-rich classical HL, and 2 of 3 with nodular lymphocyte-predominant HL. Only limited numbers of patients with non-HL expressed FoxO3a: 4 of 66 with diffuse large B-cell lymphoma, 1 of 20 with follicular lymphoma, and 1 of 5 with peripheral T-cell lymphoma, not otherwise specified. No FoxO3a expression was detected in patients with mantle cell lymphoma (n=3), extranodal marginal zone B-cell lymphoma (n=3), mediastinal large B-cell lymphoma (n=1), NK/T cell lymphoma (n=5), anaplastic large cell lymphoma (n=2), or T-lymphoblastic lymphoma/leukemia (n=2). These results suggest that FoxO3a is expressed mostly in patients with HL, but not in patients with non-HL. FoxO3a expression was limited to a small number of Hodgkin cells in a quiescent state. FoxO3a may be a CIC marker of HL, but not of non-HL.
    Pathology - Research and Practice 08/2013; · 1.21 Impact Factor
  • European journal of dermatology : EJD. 11/2012;
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    ABSTRACT: Diffuse large B cell lymphoma (DLBCL) occasionally shows an interfollicular pattern of proliferation (DLBCL-IF) preserving lymphoid follicles. In this study, clinicopathological findings in 31 cases of DLBCL-IF were analysed. The study group comprised 20 males and 11 females, with ages ranging from 41 to 87 (median 69) years. The primary site was lymph node in 25 cases, and unknown in six due to advanced stage at diagnosis. Eight cases were clinical Stage I, 10 were Stage II, four Stage III, and nine Stage IV. A polymorphous pattern of proliferation containing large B cells and inflammatory cells was found in about 60% of cases. The overall survival rate of the DLBCL-IF patients was better than that of a DLBCL control group (log-rank test; P < 0.05). Multivariate analysis revealed that an interfollicular pattern of proliferation showed marginal significance for favourable prognosis (P = 0.069). Immunohistochemical double staining with antibodies for HLA-DR/CD68 (markers for M1-tumour-associated macrophage [M1-TAM]) or CD163/CD68 (M2-TAM) revealed that all DLBCL-IF patients with a low M2 count were alive at the end of observation. These findings suggest that DLBCL-IF is a clinicopathological entity distinct from ordinary DLBCL. The possible origin of tumour cells in DLBCL-IF from marginal zone B cells is discussed.
    Histopathology 02/2012; 60(6):924-32. · 2.86 Impact Factor
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    ABSTRACT: To evaluate the role of tumour-associated macrophages (TAMs) of the M1 and M2 types in the behaviour of diffuse large B-cell lymphoma (DLBCL). Double immunohistochemical staining of HLA-DR/CD68 (M1) or CD163/CD68 (M2) was performed in 101 cases of DLBCL. CD68+ cells represent the total number of TAMs. The average number of double-positive cells was counted, and the cut-off value was set at the mean number of counts, i.e. 30.7 and 27.0 for M1 TAMs and M2 TAMs, respectively. That for total TAMs was set at the 90th percentile number of total counts, i.e. 132.3. Cases were categorized into three pairs: high (34 cases) and low (67 cases) M1 TAM groups, high (39 cases) and low (62 cases) M2 TAM groups, and high (10 cases) and low (91 cases) total TAM groups. The difference in overall survival rates was statistically significant between the high and low M2 TAM groups (P < 0.01) and between the high and low total TAM groups (P < 0.05). Multivariate analysis revealed that the presence of a bulky mass and a higher number of M2 TAMs were significant factors for poor prognosis (P < 0.05). Estimation of specific type of macrophages, of the M1 and M2 types, is superior to the estimation of TAMs as a whole (CD68+ cells) for prediction of the prognosis of DLBCL patients.
    Histopathology 01/2012; 60(2):313-9. · 2.86 Impact Factor
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    ABSTRACT: To evaluate roles of tumor-associated macrophages (TAMs) for prognosis of classical Hodgkin lymphoma (CHL). Expression of markers for TAMs, CD68, HLA-DR, CD163, HLA-DR/CD68 (M1), and CD163/CD68 (M2) was immunohistochemically examined in 82 cases with CHL. Positively stained cells were counted and correlation of number of TAMs and patients' survival time was analyzed. Number of CD163+ cells and M2 cells was significantly correlated with shorter overall survival (P < 0.05), while it was marginally significant for CD68+ cells (P = 0.0827). HLA-DR + cells and M1 cells showed no significant correlation with overall survival. When confined to mixed cellularity subtype, number of M1 cells was correlated with favorable prognosis (P < 0.05), while M2 did not (P = 0.7). Older age and male sex were unfavorable factors for prognosis. At multivariate analysis, number of CD163+ cells, M2+ cells, and age were independent factors for poor overall survival (P = 0.03, 0.02, and 0.01, respectively). CD163+ cells and M2 cells might work to be tumor promotive in CHL. M1 cells might be tumor suppressive in mixed cellularity type.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 08/2011; 459(4):361-6. · 2.68 Impact Factor
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    ABSTRACT: Objectives:  The presence of B-cell clones in 76 cases with peripheral T-cell lymphoma (PTCL) and precursor T-lymphoblastic lymphoma (T-LBL) and its correlation with Epstein-Barr virus (EBV) was studied. Methods:  DNA was extracted from paraffin sections and/or fresh-frozen samples and then used for clonality analysis using a modified BIOMED-2 polymerase chain reaction (PCR)-based method. Results:  T- and B-cell clones were detected in 59 (77.6%) and 14 (18.4%) of 76 patients, respectively: 90% and 30% of cases with PTCL, not otherwise specified, 76.4% and 17.6% of cases with angioimmunoblastic T-cell lymphoma, 77% and 7.6% of cases with adult T-cell lymphoma, 50% and 0% of cases with anaplastic large T-cell lymphoma, 62.5% and 12.5% of cases with T-LBL, and 50% and 0% of cases with intestinal T-cell lymphoma, respectively. Histological and immunohistochemical analyses revealed the presence of large B cells in lesional tissues, which were occasionally monoclonal. The presence of B-cell clones was highly associated with EBV positivity, as revealed by in situ hybridization. In two cases that were evaluated by serial histological and molecular examination, EBV-positive cells persisted in one and disappeared in the other. Conclusions:  These findings suggest a role for EBV in the evolution of B-cell clones in T-cell lymphomas.
    European Journal Of Haematology 03/2011; 86(5):412-9. · 2.55 Impact Factor
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    ABSTRACT: According to previous reports, the frequency of Epstein-Barr virus (EBV) positivity in diffuse large B-cell lymphoma is higher in East Asia (approximately 9%) than in Western countries. The presence of the EBV genome was examined in diffuse large B-cell lymphoma patients registered with the Osaka Lymphoma Study Group (OLSG) in Osaka, Japan, situated in East Asia. The EBV-positive rate was examined with in situ hybridization (ISH) in 484 immunocompetent diffuse large B-cell lymphoma patients registered with OLSG. The male-to-female ratio was 1.29, with ages ranging from 16 to 95 (median, 68) years. ISH with EBV-encoded small RNAs (EBER) probes revealed positive signals in the nuclei of tumor cells: the frequency of positively stained cells among all tumor cells was almost none in 458 cases, 5-10% in 5, 10-20% in 5, 20-50% in 11, and >50% in 5. When the frequency was >20% or >50%, the EBV-positive rate in the present series (3.3% or 1.0%) was rather similar to that reported in Western cases. Careful evaluation of patient backgrounds, including age distribution, type of lymphomas, exclusion of immunocompromised patients, and establishment of definite criteria for EBV positivity (>20%, >50%, or almost all tumor cells) are essential in comparing geographical differences.
    Journal of Medical Virology 02/2011; 83(2):317-21. · 2.37 Impact Factor
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    ABSTRACT: Aldehyde dehydrogenase (ALDH) 1 is expressed in various stem/progenitor cells, including cancer-initiating cells (CICs). In the present study, ALDH1 expression was immunohistochemically examined in diffuse large B-cell lymphoma (DLBCL). Unexpectedly, ALDH1 expression was occasionally detected in stromal cells, but not in lymphoma cells. Positively stained cells were CD68(+) cells with voluminous cytoplasm and fascin(+) cells with reticular morphology, designated as macrophages and dendritic cells (DCs), respectively. The presence of ALDH1(+) macrophages was not correlated with stage, response to therapies and prognosis. However, cases with ALDH1(+) DCs were mostly nodal, which showed a poorer response to therapies and a worse overall survival rate than cases without ALDH1(+) DCs. The presence of ALDH1(+) DCs appears to be involved in the malignant potential of DLBCL in lymph node.
    Experimental and therapeutic medicine 01/2011; 2(4):591-594. · 0.34 Impact Factor
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    Journal of Hematology & Oncology 01/2011; 4:14. · 4.46 Impact Factor
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    ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) involving spinal epidural space (SEDLBCL) is relatively rare, constituting 1.8% of DLBCLs in Osaka, Japan. The aim of this study was to analyze SEDLBCL cases for their clinical and histopathologic findings, including an association with Epstein-Barr virus (EBV) and immunohistochemical characteristics. We analyzed the clinicopathologic findings of 27 SEDLBCL cases. They consisted of 16 males and 11 females, their age ranging from 37-86 years (median 64 years). Eight patients had stage I disease, 3 had stage II, 5 had stage III, and 11 had stage IV. Based on the staining pattern for anti-CD10, bcl-6, and MUM-1, the cases were categorized into 17 cases of the germinal center B-cell (GCB) type and nine of the non-GCB type. There was a 4%-positive rate for EBV in the tumor cells. When compared to nodal DLBCL, the frequency of patients with a high performance status (PS) is higher in SEDLBCL. Compared to the DLBCL of the central nervous system (CNS), the frequency of cases with high stage, 2 or more extranodal lesions, high international prognostic index (IPI), and GCB-type is higher in SEDLBCL. There were no significant differences in the histologic features between SEDLBCL and nodal/CNS DLBCL. Univariate analysis revealed that advanced stage was an unfavorable factor for overall survival (P=0.060). SEDLBCL is different from nodal and CNS DLBCL, but an association with EBV is unlikely in every group.
    Pathology - Research and Practice 07/2010; 206(7):439-44. · 1.21 Impact Factor
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    ABSTRACT: Lymphoproliferative disorder (LPD) with polymorphous composition of proliferation (polymorphous LPD), containing large lymphoid cells together with small lymphocytes, plasma cells, macrophages, and/or eosinophils, is found in individuals with immunodeficiency conditions. Clinicopathological findings in 19 cases of polymorphous LPD registered with the Osaka Lymphoma Study Group, Osaka, Japan, were analyzed; they represented 0.4% of the registered cases. In six cases, there was a history of rheumatoid arthritis; five of them had received immunosuppressive agents. There were no acquired immunodeficiency syndrome cases or organ transplant recipients. Southern blotting and/or polymerase chain reaction (PCR)-based clonality analysis revealed monoclonal B cell and T cell proliferation in eight and six cases (B- and T-LPD), respectively, and polyclonality in one. In B-LPD, there was polymorphous proliferation, containing large B-lymphoid cells, while medium-to-large T lymphoid cells with occasional eosinophilic infiltration were seen in T-LPD. Epstein-Barr virus (EBV) was detected in three of eight B-LPD, four of six T-LPD, and one of one polyclonal LPD. The prognosis was not favorable; the 3-year overall survival rate was 49.7 +/- 17.3%. Thus, polymorphous LPD is relatively rare in Japan and is a heterogeneous disease with monoclonal proliferation of B or T cells; additionally, it is occasionally EBV-associated, and behaves as an aggressive lymphoma.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 03/2010; 456(3):269-76. · 2.68 Impact Factor
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    ABSTRACT: The aim of this study was to clarify whether diffuse large B-cell lymphoma (DLBCL) with a high number of epithelioid histiocytes (DLBCL-EH) could have distinctive clinicopathological characteristics. Clinicopathological findings in 22 cases with DLBCL-EH and, as a control, 96 cases with ordinary type of DLBCL were analyzed. There were ten men and 12 women with ages ranging from 38 to 91 (median, 64) years. The primary site was lymph node in 16 cases, extranodal organs in three, and unknown in three. Stage of disease was I in five cases, II in three, III in nine, and IV in five. Histologically, there was a diffuse proliferation of large lymphoid cells admixed with numerous clusters of epithelioid histiocytes sprinkling throughout the lesions. Immunohistochemically, the large lymphoid cells were CD20(+), CD15(-), and CD3(-) and positive for CD10, bcl-6, and MUM1 in nine (41%), eight (36%), and 12 (55%) of 22 cases, respectively. Epstein-Barr virus positive rate was higher in DLBCL-EH (23.8%) than that in ordinary DLBCL (4.5%; P<0.05). Clonality analysis revealed monoclonal bands in all of the examined 20 cases with DLBCL-EH. Multivariate analysis revealed the prominent epithelioid reaction to be an independent factor for favorable prognosis. These findings suggest that DLBCL-EH could be a specific morphological variant of DLBCL associated with a better prognosis.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 09/2009; 455(3):285-93. · 2.68 Impact Factor
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    ABSTRACT: A 69-year-old man presented with lymph node swelling in the right inguinal region. A biopsy was made (LN1) and diagnosed as peripheral T-cell lymphoma. The lesion remitted completely over a period of about 51 months after combination chemotherapy, but erythematous papules, systemic lymphadenopathy, and fever of 38 degrees appeared. Skin (S1) and lymph nodes (LN2) were biopsied. Erythematous papules once disappeared spontaneously, but appeared again and were biopsied (S2). LN1 displayed the typical histologic and immunohistochemical features of Lennert lymphoma, i.e., diffuse proliferation of small to large lymphoid cells of CD3+, CD4+, CD8- immunophenotype accompanied by numerous clusters of epithelioid histiocytes. In LN2, the large cells with CD3+, CD4+, CD8- decreased in number, while numerous CD20+ large cells were discernible. Clonality analysis revealed the persistent presence of an identical T-cell clone in LN1 and LN2. Clonal bands of immunoglobulin heavy (IgH) chain gene were detected in LN2 but not in LN1. S1 and S2 showed diffuse proliferation of small to large lymphoid cells of CD20-, CD3+, CD4+, CD8- in the upper dermis, with obvious epidermotropism. Clonality analysis revealed the presence of a T-cell clone identical to LN1 and LN2 with no B-cell clone, indicating the recurrence of PTCL. In situ hybridization (ISH) for Epstein-Barr virus (EBV) genome revealed that positive signals in the nucleus of large B-lymphoid cells appeared only in LN2. Taken together, EBV-positive large B-cell lymphoma appeared transiently in the course of "Lennert lymphoma".
    Pathology - Research and Practice 06/2009; 206(3):185-90. · 1.21 Impact Factor
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    ABSTRACT: An 80-year-old man presented with continuous spike fever and night sweats. Computed tomographic scans revealed a poorly demarcated mass in the upper part of the right kidney, which was resected. At surgery, tumorous lesions were not found in the abdominal cavity. Serum IgG4 level measured after surgery was 40.1mg/dl. Macroscopically, renal parenchyma of the upper part was replaced by an irregularly shaped grayish-white lesion of elastic, firm consistency. Histologically, the lesion consisted mostly of fibrous tissue in which small lymphoid cells, often with formation of aggregates, were evident. IgG4-positive plasma cells were few in number. Careful macroscopic examination revealed several minute nodules, which histologically consisted of large lymphoid cells, small lymphoid cells, and macrophages. These large lymphoid cells were positive for CD20 and contained Epstein-Barr virus (EBV) genome. Taken together, a diagnosis of EBV-positive B-cell lymphoproliferative disease (LPD) developing in inflammatory pseudotumor (IPT) of the kidney was made. This is the first report of B-LPD in IPT of the kidney. In addition, a presence of EBV in renal lymphoma cells has not yet been reported.
    Pathology - Research and Practice 06/2009; 206(2):134-7. · 1.21 Impact Factor
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    ABSTRACT: Change of CD20 expression was examined in cases of diffuse large B-cell lymphoma (DLBCL). CD20 expression after treatment with anti-CD20 antibody (rituximab, Rx) for DLBCL was examined in 23 cases who received serial biopsy by immunohistochemistry (IHC) and flow cytometry (FCM). CD20- by IHC and/or FCM was defined as CD20-. Four cases were CD20- at initial biopsy but became CD20+ after chemotherapy with Rx (CH-R) (group A). Recurrent tumors in three group A cases became resistant to CH-R. Initial and recurrent tumors were CD20+ before and after CH-R in 17 cases (group B). Tumors before CH-R were CD20- in two cases (group C) and continued to be CD20- in one and turned CD20+ in the other with survival time after the relapse of 8 and 23 months, respectively. Evaluation of CD20 expression with immunohistochemical and flow cytometric methods is used for the prediction of responsiveness of relapsed DLBCL for CH-R.
    Case Reports in Oncology 01/2009; 2(3):194-202.
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    ABSTRACT: The present study examines clinicopathologic findings and their association with the Epstein-Barr virus (EBV) in Waldeyer's ring lymphomas (WRLs) from Indonesia (91 cases), P.R. China (31 cases), Korea (101 cases) and Japan (61 cases). Waldeyer's ring (WR) was categorized into upper and lower parts comprising the pharyngeal and tubal tonsils (upper WR) or palatine and lingual tonsils (lower WR), respectively. Diffuse large B-cell lymphoma (DLBCL) pre-dominated in the lower WR in all countries at a frequency of 78.9-100%. Natural killer/T-cell lymphoma (NKTCL) was predominant in the upper WR in China, Korea and Japan at a frequency of 50-62.5%, while in Indonesia it occcurred at a frequency of less than 10%. On the whole, patients with NKTCL were significantly younger (median 43 years) than those with DLBCL (57 years). Patients with DLBCL in the lower WR were significantly younger in Indonesia (median 50 years) than in China (63 years) or Japan (69 years). The percentage of EBV-positive cases was much higher in NKTCL (78.6-100%) than in DLBCL (2.2-6%). This study evaluates the differences between East and Southeast Asian countries in terms of histologic type and age distribution in WRLs categorized by the location of the lesions in WR.
    Molecular Medicine Reports 01/2008; 1(5):651-5. · 1.17 Impact Factor
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    ABSTRACT: Infliximab is a chimeric monoclonal antibody that binds specifically and directly to human tumor necrosis factor � (TNF-� ), a key player in the inflammatory response, and neutralizes its biologic activity. In 1998, the US Food and Drug Administration approved infliximab for the treatment of active Crohn disease and for rheumatoid arthritis (RA) with moderate to high severity [1]. This therapy dramatically improved the complaints of RA patients, although an increase in the risk for developing lymphoproliferative disorders (LPD) under short-term use in the United States was indicated [1]. In Japan, infliximab therapy has been approved for Crohn disease since 2002 and for RA with severe activity since 2003. Because the use of infliximab is becoming popular, LPD development is expected to increase in Japan among patients with RA and with Crohn disease. Recently, we experienced a case of infliximab-associated LPD in a Japanese RA patient who received anti‐TNF-� therapy. This case is the first of a Japanese patient with infliximabassociated LPD to be described in the literature. A 58-year-old Japanese woman presented with fever and an inguinal mass of 1 month’s duration. Her disease had been diagnosed as RA at the age of 40 years. She had first been treated with a nonsteroidal anti-inflammatory drug and then was treated with bucillamine, methotrexate (MTX), cyclosporine, and infliximab. MTX (5-7.5 mg/wk) with a cumulative dose of 1214 mg was administered over a 10-year period. Infliximab was started at a dosage of 45 mg/wk (cumulative dose of 1080 mg) 9 months ago until the appearance of cervical lymph node swelling. Physical and roentgenographic examinations revealed systemic lymphadenopathy involving the cervical, para-aortic, and inguinal regions. The inguinal lymph node was biopsied and histologically diagnosed as
    International Journal of Hematology 06/2005; 81(4):356-7. · 1.68 Impact Factor
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    ABSTRACT: IB4 is a lymphoblastoid cell line frequently used for the functional analysis of the latent genes of EBV. Previous study indicated that EBV whole genome is integrated tandemly as the linear viral genome into host genome of IB4, although sites of integration have not been determined. Through cloning of the junctional regions between EBV and host genomes, one of the integration sites was identified on the BamHI-C fragments around oriP sequences and another on the EcoRI-I fragment. Both of the integration sites were located on the clone RP11-119H12 of chromosome 4q25 and separated approximately 6.5 kbp from each other. The integration sites identified were apart from the genes of the host genome, indicating that both host gene and EBV latent genes are not altered by the integration event.
    Virus Research 04/2005; 108(1-2):133-8. · 2.75 Impact Factor