The tumor marker Fascin is strongly induced by the Tax oncoprotein of HTLV-1 through NF-κB signals

AbstractOncogenic transformation of CD4+ T cells by human T-cell lymphotropic virus type 1 (HTLV-1) is understood as the initial step to adult T-cell leukemia/lymphoma, a process that is mainly initiated by perturbation of cellular signaling by the viral Tax oncoprotein, a potent transcriptional regulator. In search of novel biomarkers with relevance to oncogenesis, we identified the tumor marker and actin-bundling protein Fascin (FSCN1) to be specifically and strongly up-regulated in both HTLV-1–transformed and adult T-cell leukemia/lymphoma patient-derived CD4+ T cells. Fascin is important for migration and metastasis in various types of cancer. Here we report that a direct link can exist between a single viral oncoprotein and Fascin expression, as the viral oncoprotein Tax was sufficient to induce high levels of Fascin. Nuclear factor-κB signals were important for Tax-mediated transcriptional regulation of Fascin in T cells. This suggests that Fascin up-regulation by Tax contributes to the development of HTLV-1–associated pathogenesis.

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Prevention of Adult T-Cell Leukemia-Like Lymphoproliferative Disease in Rats by Adoptively Transferred T Cells from a Donor Immunized with Human T-Cell Leukemia Virus Type 1 Tax-Coding DNA Vaccine

Journal of Virology ◽

10.1128/jvi.74.20.9610-9616.2000 ◽

2000 ◽

Vol 74 (20) ◽

pp. 9610-9616 ◽

Cited By ~ 47

Author(s):

Takashi Ohashi ◽

Shino Hanabuchi ◽

Hirotomo Kato ◽

Hiromi Tateno ◽

Fumiyo Takemura ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Dna Vaccine ◽

Leukemia Virus ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Adult T Cell Leukemia ◽

Human T Cell

ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL) in infected individuals after a long incubation period. To dissect the mechanisms of the development of the disease, we have previously established a rat model of ATL-like disease which allows examination of the growth and spread of HTLV-1 infected tumor cells, as well assessment of the effects of immune T cells on the development of the disease. In the present study, we induced HTLV-1 Tax-specific cytotoxic T lymphocyte (CTL) immunity by vaccination with Tax-coding DNA and examined the effects of the DNA vaccine in our rat ATL-like disease model. Our results demonstrated that DNA vaccine with Tax effectively induced Tax-specific CTL activity in F344/N Jcl-rnu/+ (nu/+) rats and that these CTLs were able to lyse HTLV-1 infected syngeneic T cells in vitro. Adoptive transfer of these immune T cells effectively inhibited the in vivo growth of HTLV-1-transformed tumor in F344/N Jcl-rnu/rnu (nu/nu) rats inoculated with a rat HTLV-1 infected T cell line. Vaccination with mutant Tax DNA lacking transforming ability also induced efficient anti-tumor immunity in this model. Our results indicated a promising effect for DNA vaccine with HTLV-1 Tax against HTLV-1 tumor development in vivo.

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Human T-cell leukemia virus type-1 (HTLV-1) Tax is expressed at the same level in infected cells of HTLV-1-associated myelopathy or tropical spastic paraparesis patients as in asymptomatic carriers but at a lower level in adult T-cell leukemia cells

Blood ◽

10.1182/blood.v85.7.1865.bloodjournal8571865 ◽

1995 ◽

Vol 85 (7) ◽

pp. 1865-1870 ◽

Cited By ~ 54

Author(s):

Y Furukawa ◽

M Osame ◽

R Kubota ◽

M Tara ◽

M Yoshida

Keyword(s):

T Cells ◽

T Cell ◽

Leukemia Virus ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Asymptomatic Carriers ◽

Adult T Cell Leukemia ◽

Human T Cell ◽

T Cell Leukemia Virus

Patients with human T-cell leukemia virus type-1 (HTLV-1)-associated myelopathy (HAM/TSP) generally harbor a much greater population of HTLV-1-infected T cells in peripheral blood mononuclear cells (PBMCs) than asymptomatic carriers. These cells are not malignant but frequently proliferate clonally. To investigate the possibility that higher expression of the viral activator Tax induces preferential proliferation of infected nonmalignant T cells in HAM/TSP patients, the expression of Tax mRNA in fresh PBMCs was analyzed by reverse transcriptase-mediated polymerase chain reaction. Total amount of Tax mRNA was higher in HAM/TSP patients than in carriers, but the expression level was almost the same as that in asymptomatic carriers when compared per infected cell. The expression levels in adult T-cell leukemia patients were significantly lower than those in HAM/TSP patients and asymptomatic carriers. These results indicate that tax gene is not expressed at a continuously high level in HAM/TSP patients who carry a high population of infected T cells, even in those with clonally proliferated infected T cells.

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Detection of human T-cell lymphotropic virus type I-specific cytotoxic T-cells may predict treatment responses in adult T-cell leukemia/lymphoma patients

Annals of Hematology ◽

10.1007/s00277-017-3052-4 ◽

2017 ◽

Vol 96 (9) ◽

pp. 1587-1588 ◽

Cited By ~ 1

Author(s):

Hiroshi Ureshino ◽

Kazuharu Kamachi ◽

Masaharu Miyahara

Keyword(s):

T Cells ◽

T Cell ◽

Virus Type ◽

Cytotoxic T Cells ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

Human T Cell ◽

Treatment Responses

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Augmented expression of programmed death-1 in both neoplastic and non-neoplastic CD4+ T-cells in adult T-cell leukemia/lymphoma

International Journal of Cancer ◽

10.1002/ijc.23042 ◽

2007 ◽

Vol 121 (12) ◽

pp. 2585-2590 ◽

Cited By ~ 61

Author(s):

Takatoshi Shimauchi ◽

Kenji Kabashima ◽

Daiki Nakashima ◽

Kazunari Sugita ◽

Yoko Yamada ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

Programmed Death ◽

Programmed Death 1

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Frequent expression of CCR4 in adult T-cell leukemia and human T-cell leukemia virus type 1–transformed T cells

Blood ◽

10.1182/blood.v99.5.1505 ◽

2002 ◽

Vol 99 (5) ◽

pp. 1505-1511 ◽

Cited By ~ 188

Author(s):

Osamu Yoshie ◽

Ryuichi Fujisawa ◽

Takashi Nakayama ◽

Hitomi Harasawa ◽

Hideaki Tago ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Leukemia Virus ◽

Flow Cytometric Analysis ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Adult T Cell Leukemia ◽

Human T Cell ◽

T Cell Leukemia Virus

Chemokines and chemokine receptors play important roles in migration and tissue localization of various lymphocyte subsets. Here, we report the highly frequent expression of CCR4 in adult T-cell leukemia (ATL) and human T-cell leukemia virus type 1 (HTLV-1)–immortalized T cells. Flow cytometric analysis revealed that ATL and HTLV-1–immortalized T-cell lines consistently expressed CCR4. Inducible expression of HTLV-1 transcriptional activator tax in a human T-cell line Jurkat did not, however, up-regulate CCR4 mRNA. In vitro immortalization of peripheral blood T cells led to preferential outgrowth of CD4+ T cells expressing CCR4. We further demonstrated highly frequent expression of CCR4 in fresh ATL cells by (1) reverse transcriptase–polymerase chain reaction (RT-PCR) analysis of CCR4 expression in peripheral blood mononuclear cells (PBMCs) from patients with ATL and healthy controls; (2) flow cytometric analysis of CCR4-expressing cells in PBMCs from patients with ATL and healthy controls; (3) CCR4 staining of routine blood smears from patients with ATL; and (4) an efficient migration of fresh ATL cells to the CCR4 ligands, TARC/CCL17 and MDC/CCL22, in chemotaxis assays. Furthermore, we detected strong signals for CCR4, TARC, and MDC in ATL skin lesions by RT-PCR. Collectively, most ATL cases have apparently derived from CD4+ T cells expressing CCR4. It is now known that circulating CCR4+ T cells are mostly polarized to Th2 and also contain essentially all skin-seeking memory T cells. Thus, HTLV-1–infected CCR4+ T cells may have growth advantages by deviating host immune responses to Th2. CCR4 expression may also account for frequent infiltration of ATL into tissues such as skin and lymph nodes.

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Increased density of ecto 5' nucleotidase antigen on leukemic T cells from patients with cutaneous T-cell lymphoma and adult T-cell leukemia/lymphoma

Blood ◽

10.1182/blood.v74.7.2486.bloodjournal7472486 ◽

1989 ◽

Vol 74 (7) ◽

pp. 2486-2492

Author(s):

Y Fukunaga ◽

SS Evans ◽

M Yamamoto ◽

Y Ueda ◽

K Tamura ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

T Cell Subsets ◽

Cutaneous T Cell Lymphoma ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia

Malignant CD4+ T cells in adult T-cell leukemia/lymphoma (ATL) and cutaneous T-cell lymphoma (CTCL) express a number of cell surface molecules that are upregulated on normal T cells activated by foreign antigen. In this report we describe an interesting exception to the parallel phenotypic features of activated T cells and malignant CD4+ T cells. A monoclonal antibody (MoAb; termed 27.2) that was raised to HTLV-1+, CD4+25+ leukemic T cells stained weakly 25% of peripheral T cells, including approximately 50% of CD8+ T cells and 20% of CD4+ T cells. Flow cytometry analysis indicated that the surface density of the 27.2 antigen was unchanged or diminished when normal T cells were activated by antigen. However, 3/4 Sezary cases and 4/8 cases of ATL had relatively high densities of the 27.2 antigen. Immunoprecipitation and sodium dodecylsulfate polyacrylamide gel electrophoresis of the NP- 40-solubilized membranes of surface-iodinated ATL cells indicated that MoAb 27.2 reacted with a 75 Kd molecule. The size and distribution of the 27.2 antigen on T cell subsets suggested that it might be the enzyme ecto-5′ nucleotidase (NT), a phosphatidylinositol-linked enzyme that catalyzes dephosphorylation of monophosphate nucleotides to their respective nucleosides. This was confirmed by demonstrating that lymphocyte ecto-5′NT activity was blocked partially and inhibited completely by preincubating cells with MoAb 27.2 for 1 hour at 4 degrees C and 24 hours at 37 degrees C, respectively. When used with a second MoAb (27.1) to a novel T cell activation antigen found on all CTCL and ATL leukemias examined, 27.2 was found to discriminate between normal and leukemic T cells in two patients with ATL. These studies suggest that ecto-5′NT has diagnostic value in T cell malignancies and may be aberrantly expressed in some cases of ATL and CTCL.

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Human T-cell leukemia virus type I Tax associates with and is negatively regulated by the NF-kappa B2 p100 gene product: implications for viral latency

Molecular and Cellular Biology ◽

10.1128/mcb.14.2.1374-1382.1994 ◽

1994 ◽

Vol 14 (2) ◽

pp. 1374-1382

Author(s):

C Béraud ◽

S C Sun ◽

P Ganchi ◽

D W Ballard ◽

W C Greene

Keyword(s):

T Cells ◽

T Cell ◽

Virus Type ◽

Leukemia Virus ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Adult T Cell Leukemia ◽

Human T Cell

Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of the adult T-cell leukemia, an aggressive and often fatal malignancy of activated human CD4 T cells. HTLV-I encodes an essential 40-kDa protein termed Tax that not only transactivates the long terminal repeat of this retrovirus but also induces an array of cellular genes. Tax-mediated transformation of T cells likely involves the deregulated expression of various cellular genes that normally regulate lymphocyte growth produced by altered activity of various endogenous host transcription factors. In particular, Tax is capable of modulating the expression or activity of various host transcription factors, including members of the NF-kappa B/Rel and CREB/ATF families, as well as the cellular factors HEB-1 and p67SRF. An additional distinguishing characteristic of HTLV-I infection is the profound state of viral latency that is present in circulating primary leukemic T cells. In this study, we demonstrate that HTLV-I Tax can physically associate with p100, the product of the Rel-related NF-kappa B2 gene, both in transfected cells and in HTLV-I-infected leukemic T-cell lines. Furthermore, the physical interaction of Tax with p100 leads to the inhibition of Tax-induced activation of the HTLV-I and human immunodeficiency virus type 1 long terminal repeats, reflecting p100-mediated cytoplasmic sequestration of the normally nuclearly expressed Tax protein. In contrast, a mutant of Tax that selectively fails to activate nuclear NF-kappa B expression does not associate with p100. Together, these results suggest that the cytoplasmic interplay of Tax and p100 may play an important role in the initiation and maintenance of HTLV-1 latency observed in adult T-cell leukemia.

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