Human T cell leukemia virus type 1 (HTLV-1), an etiological factor that causes adult T cell leukemia and lymphoma (ATL), infects over 20 million people worldwide. About 1 million of HTLV-1-infected patients develop ATL, a highly aggressive non-Hodgkin's lymphoma without an effective therapy. The pX region of the HTLV-1 viral genome encodes an oncogenic protein, Tax, which plays a central role in transforming CD4+ T lymphocytes by deregulating oncogenic signaling pathways and promoting cell cycle progression. Expression of Tax following viral entry is critical for promoting survival and proliferation of human T cells and is required for initiation of oncogenesis. Tax exhibits diverse functions in host cells, and this oncoprotein primarily targets IκB kinase complex in the cytoplasm, resulting in persistent activation of NF-κB and upregulation of its responsive gene expressions that are crucial for T cell survival and cell cycle progression. We here review recent advances for the pathological roles of Tax in modulating IκB kinase activity. We also discuss our recent observation that Tax connects the IκB kinase complex to autophagy pathways. Understanding Tax-mediated pathogenesis will provide insights into development of new therapeutics in controlling HTLV-1-associated diseases.
Autophagy ; CD4-Positive T-Lymphocytes ; metabolism ; virology ; Cell Cycle ; Cell Transformation, Neoplastic ; genetics ; Gene Expression Regulation, Neoplastic ; Gene Products, tax ; genetics ; metabolism ; Human T-lymphotropic virus 1 ; physiology ; Humans ; I-kappa B Kinase ; genetics ; metabolism ; Leukemia-Lymphoma, Adult T-Cell ; genetics ; metabolism ; virology ; Membrane Microdomains ; metabolism ; virology ; NF-kappa B ; genetics ; metabolism ; Protein Binding ; Signal Transduction ; genetics

Recent studies have suggested a probable association between Epstein-Barr virus (EBV) and nasal/nasopharyngeal T cell lymphomas but the role of oncogenes or tumor suppressor genes is poorly understood. We have studied the frequency of p53 expression and its relation to the EBV infection in 33 Korean patients with head and neck (H&N) lymphomas. All cases (23 B cell & 10 T cell) were immunostained for p53 protein using the mAb D07 (Novocastra) and the avidin biotin peroxidase method. EBER in situ hybridization was performed using a fluorescein conjugated EBV oligonucleotide probe (Dako). Among 33 lymphomas, 16 cases stained positively for p53 protein. P53 expression was frequent both in higher grade lymphomas and in advanced stage. Nine cases were EBER positive, EBER was more commonly found in T cell lymphomas than in B cell lymphomas (70% vs 8.7%). EBER positive lymphomas showed a higher frequency of p53 positivity than EBER negative lymphomas (78% vs 38%), although the difference was not statistically significant (p = 0.095). These findings indicate altered expression of p53 protein occurs in H&N lymphomas, especially in late event lymphoma progression and appears to play a role in the development of EBER positive T cell lymphomas.
Follow-Up Studies ; Gene Expression ; Genes, p53 ; Head and Neck Neoplasms/genetics/*metabolism/*virology ; Herpesviridae Infections/genetics/*metabolism ; *Herpesvirus 4, Human ; Human ; Lymphoma, T-Cell/genetics/*metabolism/*virology ; Prognosis ; Protein p53/*biosynthesis ; Support, Non-U.S. Gov't ; Tumor Virus Infections/genetics/*metabolism

OBJECTIVETo investigate the expression of matrix metalloproteinase 9 (MMP9) in mucosal natural killer/T cell and mature T cell lymphomas and its relation to Epstein-Barr virus (EBV) infection.

METHODSThe expression of MMP9 and EBV-encoded RNA (EBER) were detected by immunohistochemistry and in situ hybridization in 59 cases of mucosal natural killer/T cell and mature T cell lymphomas.

RESULTSThe positivity rates of MMP9 and EBERs were 83.05% and 72.88% respectively. The positivity rate of EBERs was correlated with histopathological subtype (P<0.05), but not with clinical stage, vascular invasion or the patients' survival time (P>0.05). The expression level of MMP9 was not correlated with the clinical stage, vascular invasion or survival time (P>0.05). No significant correlation was found between MMP9 expression and EBV infection.

CONCLUSIONEBV may play an important role in the development of mucosal natural killer/T cell and mature T cell lymphomas and promote disease progression by up-regulating MMP9 expression indirectly. Elimination of EBV infection may be helpful to prevent the development of lymphoma.

Female ; Gene Expression Regulation, Neoplastic ; Herpesvirus 4, Human ; physiology ; Humans ; Lymphoma, T-Cell ; genetics ; pathology ; virology ; Male ; Matrix Metalloproteinase 9 ; metabolism ; Mucous Membrane ; pathology ; virology ; Natural Killer T-Cells ; pathology ; virology

The incidence of posttransplantation lymphoproliferative disorders (PTLDs) has increased in recent years. Although rare, various types of T-cell lymphoma have been reported and their association with Epstein-Barr virus (EBV) has been compared with B-cell PTLDs. We report a case of splenic peripheral T-cell lymphoma occurring in a 47-yr-old male patient 7 yr after renal allograft transplantation. The spleen showed sinusoidal proliferation of focal CD30 positive, large, atypical lymphoid cells. Positivity for CD3 and cytolytic granule-associated proteins was also demonstrated in the tumor cells, while anaplastic large cell lymphoma kinase (ALK) and CD8 were not expressed. Strong nuclear signals for EBV mRNA were noted by EBER1 in situ hybridization. A molecular genetic study demonstrated a rearrangement of the gamma T-cell receptor gene. To our knowledge, this case is unique in terms of a posttransplant T-cell lymphoma that shows focal CD30, cytolytic granule-associated proteins, and EBV positivity.
Antigens, CD30/genetics ; Antigens, CD30/metabolism ; Herpesvirus 4, Human/genetics ; Herpesvirus 4, Human/metabolism* ; Human ; Kidney Transplantation* ; Lymphoma, T-Cell, Peripheral/pathology ; Lymphoma, T-Cell, Peripheral/virology* ; Male ; Membrane Proteins/metabolism ; Middle Aged ; RNA, Viral ; RNA-Binding Proteins/metabolism ; Serine Endopeptidases/metabolism ; Splenic Neoplasms/pathology ; Splenic Neoplasms/virology*

OBJECTIVETo study the expression of microRNAs (miRNAs) in extranodal NK/T cell lymphoma, nasal type (EN-NK/T-NT).

METHODSTaqMan low density arrays were used to assess the expression level of 665 miRNAs in one case of EN-NK/T-NT and one normal nasopharyngeal tissue. Ninety-five miRNAs were found to be aberrantly expressed (86 being up-regulated and 9 being down-regulated) in EN-NK/T-NT, compared with normal nasopharyngeal tissue. The aberrant expression was found to be most significant in 8 miRNAs. According to the literature and miRNA database, the expression patterns of these 8 miRNAs were further analyzed in 15 cases of EN-NK/T-NT and 3 normal nasopharyngeal specimens, using the single tube TaqMan microRNA assays.

RESULTSThree of the 8 miRNAs showed statistically significant difference in the expression in EN-NK/T-NT and normal nasopharyngeal specimens. These 3 miRNAs (miR-223, 886-3p and 34c-5p) were considered to play crucial roles in hemopoiesis, cellular proliferation and apoptosis. MiR-223 and miR-886-3p were significantly over-expressed in EN-NK/T-NT (P = 0.002, P = 0.010) while miR-34c-5p was significantly under-expressed (P = 0.017).

CONCLUSIONSCertain types of miRNAs, especially those related to hemopoiesis, cellular proliferation and apoptosis, are aberrantly expressed in EN-NK/T-NT. The potential role of miRNAs in the molecular genetics of EN-NK/T-NT requires further investigation.

Adult ; Aged ; CD56 Antigen ; metabolism ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Herpesvirus 4, Human ; isolation & purification ; Humans ; Lymphoma, Extranodal NK-T-Cell ; genetics ; metabolism ; pathology ; virology ; Male ; MicroRNAs ; genetics ; metabolism ; Middle Aged ; Nasal Mucosa ; metabolism ; Young Adult

To investigate the expression of survivin gene and its relationship with Epstin-Barr virus (EBV) infection in midline T-cell lymphoma (MTL), immunohistochemistry staining method was used to examine the expression of survivin and EBV-latent membrane protein (LMP-1) in the 41 cases. In situ hybridization (ISH) was used to detect EBV-encoded RNA (EBER1/2). The results showed that the expression of survivin was positive in 26 cases of midline T-cell lymphoma, but no positive was detected in 10 cases of reactive lymphoid tissues. The positive expression ratio of survivin was 12.5% in cases of MTL with low grade of malignancy, and was 75.76% in cases of MTL with middle and high grades of malignancy, the significant difference was found between these two groups (chi(2) = 8.55, P < 0.01). Positive expression ratios of EBER1/2 and LMP-1 were 70.73% and 41.46% respectively. Survivin expression was not significantly different between EBER1/2 positive and negative cases (P > 0.05). It is concluded that survivin expression is up-regulated in MTL, and survivin positive expression rate is associated with the degree of malignancy. Survivin may play a role in the pathogenesis of the MTL by influencing cell apoptosis. EBV infection is not significantly associated with survivin expression in the MTL.
Adaptor Proteins, Signal Transducing ; Adolescent ; Adult ; Aged ; Child ; Cytoskeletal Proteins ; Epstein-Barr Virus Infections ; metabolism ; pathology ; virology ; Female ; Granuloma, Lethal Midline ; metabolism ; pathology ; virology ; Humans ; Immunohistochemistry ; In Situ Hybridization ; Inhibitor of Apoptosis Proteins ; Intracellular Signaling Peptides and Proteins ; metabolism ; LIM Domain Proteins ; Lymphoma, T-Cell ; metabolism ; pathology ; virology ; Male ; Microtubule-Associated Proteins ; biosynthesis ; Middle Aged ; Neoplasm Proteins ; biosynthesis ; Nose Neoplasms ; metabolism ; pathology ; virology ; RNA, Viral ; genetics