Retracted: A modified version of galectin-9 suppresses cell growth and induces apoptosis of human T-cell leukemia virus type I-infected T-cell lines

The human T-cell leukemia virus type I (HTLV-I) regulatory protein, Tax, has been speculated to play a major role in HTLV-I leukemogenesis. Indeed, several studies have suggested that upregulation of various cellular oncogenes and cytokines by Tax may explain the pathogenesis observed in HTLV-I–infected individuals, as well as several Tax-transgenic animal models. We report here the analysis of cytokine expression in a Tax-transgenic animal model with large granular lymphocytic (LGL) leukemia. Two different transgenic mice showed identical expression of interleukin-1α (IL-1α), IL-1β, interferon γ (IFNγ), and granulocyte-macrophage colony-stimulating factor (GM-CSF ) in peripheral tail tumors. Interestingly, LGL cell lines derived from these same tumors expressed high levels of both IFNγ and GM-CSF, which correlated with the level of Tax expression. These same LGL cell lines also expressed high levels of lymphocyte function-associated antigen-1 (LFA-1) and intracellular adhesion molecule-1 (ICAM-1). Engraftment of these LGL cell lines into severe combined immunodeficient (SCID) mice led to the development of leukemia and lymphomas. Examination of these SCID mice showed that their pathology was nearly identical to that observed in the original Tax-transgenic mouse model. Both the Tax-transgenic and engrafted SCID mouse models allow for the analysis of cellular events that are required for tumor development associated with HTLV infection and suggest that Tax expression may be responsible for the upregulation of certain cytokines and adhesion molecules that affect the infiltrating capabilities of HTLV-I–infected cells.

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Expression of FAP-1 (Fas-Associated Phosphatase) and Resistance to Fas-Mediated Apoptosis in T Cell Lines Derived from Human T Cell Leukemia Virus Type 1-Associated Myelopathy/Tropical Spastic Paraparesis Patients

AIDS Research and Human Retroviruses ◽

10.1089/aid.1998.14.261 ◽

1998 ◽

Vol 14 (3) ◽

pp. 261-267 ◽

Cited By ~ 36

Author(s):

MASAAKI ARAI ◽

MARI KANNAGI ◽

MASAO MATSUOKA ◽

TAKAAKI SATO ◽

NAOKI YAMAMOTO ◽

...

Keyword(s):

T Cell ◽

Cell Lines ◽

Leukemia Virus ◽

Spastic Paraparesis ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Human T Cell ◽

T Cell Leukemia Virus ◽

T Cell Lines

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Human T-Cell Leukemia Virus Type I Tax Activates CD69 Gene Expression.

Blood ◽

10.1182/blood.v108.11.2256.2256 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2256-2256

Author(s):

Chie Ishikawa ◽

Taeko Okudaira ◽

Tetsuro Nakazato ◽

Mariko Tomita ◽

Naoki Mori

Keyword(s):

T Cell ◽

Cell Lines ◽

Leukemia Virus ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Human T Cell ◽

Cd69 Expression ◽

T Cell Lines

Abstract The human T-cell leukemia virus type I (HTLV-I) is an oncogenic retrovirus that is etiologically linked to the genesis of adult T-cell leukemia (ATL). Emerging evidence suggests that the pathogenicity of ATL involves suppression of the overall immune response, although the underlying mechanism remains unclear. In this study, we demonstrated that HTLV-I transactivator Tax induces the aberrant expression of CD69, an early leukocyte activation molecule that plays an important role in downregulation of the immune response. In a panel of HTLV-I-infected T-cell lines, CD69 expression was highly elevated compared to HTLV-I-negative T-cell lines at both mRNA and protein levels. Furthermore, CD69 expression correlated with Tax expression. Peripheral blood mononuclear cells from ATL patients also showed an increased expression of CD69 compared with controls. In vitro infection of a T-cell line with HTLV-I was associated with CD69 expression in conjunction with the increasing Tax expression. Expression of CD69 was dependent upon Tax expression in the inducible Tax-expressing cell line JPX-9. Tax transactivated the CD69 gene promoter in a transient transfection assay. Using Tax mutants and dominant negative mutants of IκBs, IKKs, NIK, and CREB, we demonstrated that Tax-induced CD69 expression required the NF-κB and CREB signaling pathways. A series of deletion and mutation analyses of the CD69 gene promoter indicated that two NF-κB, two EGR, and a CRE sequences were critical for Tax transactivation. Electrophoretic mobility shift assay showed the formation of specific protein-DNA complexes in HTLV-I-infected T-cell lines. These results suggest that Tax directly transactivated CD69 gene expression, through multiple cis-acting elements and by the interplay of transcription factors of the NF-κB, EGR, and CREB families. Tax-induced CD69 expression may be involved in immune suppression in ATL.

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Heterogeneity of Antigen Molecules Recognized by Anti-tax1Monoclonal Antibody Lt-4 in Cell Lines Bearing Human T Cell Leukemia Virus Type I and Related Retroviruses

Japanese Journal of Cancer Research ◽

10.1111/j.1349-7006.1990.tb02554.x ◽

1990 ◽

Vol 81 (3) ◽

pp. 225-231 ◽

Cited By ~ 52

Author(s):

Yuetsu Tanaka ◽

Atsushi Yoshida ◽

Yoshinaga Takayama ◽

Hajime Tsujimoto ◽

Atsumi Tsujimoto ◽

...

Keyword(s):

T Cell ◽

Cell Lines ◽

Virus Type ◽

Leukemia Virus ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Human T Cell ◽

T Cell Leukemia Virus

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Resistance to Apo2 Ligand (Apo2L)/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Mediated Apoptosis and Constitutive Expression of Apo2L/TRAIL in Human T-Cell Leukemia Virus Type 1-Infected T-Cell Lines

Journal of Virology ◽

10.1128/jvi.79.3.1367-1378.2005 ◽

2005 ◽

Vol 79 (3) ◽

pp. 1367-1378 ◽

Cited By ~ 17

Author(s):

Takehiro Matsuda ◽

Alex Almasan ◽

Mariko Tomita ◽

Jun-nosuke Uchihara ◽

Masato Masuda ◽

...

Keyword(s):

T Cell ◽

Cell Lines ◽

Leukemia Virus ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Human T Cell ◽

T Cell Leukemia Virus ◽

Induced Apoptosis ◽

T Cell Lines

ABSTRACT Adult T-cell leukemia (ATL), a CD4+-T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1), is difficult to cure, and novel treatments are urgently needed. Apo2 ligand (Apo2L; also tumor necrosis factor-related apoptosis-inducing ligand [TRAIL]) has been implicated in antitumor therapy. We found that HTLV-1-infected T-cell lines and primary ATL cells were more resistant to Apo2L-induced apoptosis than uninfected cells. Interestingly, HTLV-1-infected T-cell lines and primary ATL cells constitutively expressed Apo2L mRNA. Inducible expression of the viral oncoprotein Tax in a T-cell line up-regulated Apo2L mRNA. Analysis of the Apo2L promoter revealed that this gene is activated by Tax via the activation of NF-κB. The sensitivity to Apo2L was not correlated with expression levels of Apo2L receptors, intracellular regulators of apoptosis (FLICE-inhibitory protein and active Akt). NF-κB plays a crucial role in the pathogenesis and survival of ATL cells. The resistance to Apo2L-induced apoptosis was reversed by N-acetyl-l-leucinyl-l-leucinyl-l-norleucinal (LLnL), an NF-κB inhibitor. LLnL significantly induced the Apo2L receptors DR4 and DR5. Our results suggest that the constitutive activation of NF-κB is essential for Apo2L gene induction and protection against Apo2L-induced apoptosis and that suppression of NF-κB may be a useful adjunct in clinical use of Apo2L against ATL.

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Transcriptional regulation of the human interleukin-6 gene promoter in human T-cell leukemia virus type I-infected T-cell lines: evidence for the involvement of NF-kappa B

Blood ◽

10.1182/blood.v84.9.2904.2904 ◽

1994 ◽

Vol 84 (9) ◽

pp. 2904-2911 ◽

Cited By ~ 50

Author(s):

N Mori ◽

F Shirakawa ◽

H Shimizu ◽

S Murakami ◽

S Oda ◽

...

Keyword(s):

T Cell ◽

Cell Lines ◽

Leukemia Virus ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Nf Kappa B ◽

Cell Leukemia Virus Type ◽

Human T Cell ◽

T Cell Lines

Abstract Freshly isolated leukemic cells from patients with adult T-cell leukemia (ATL) and human T-cell leukemia virus type I (HTLV-I)-infected T-cell lines constitutively produce high levels of interleukin-6 (IL-6) protein and mRNA. To clarify the mechanisms that lead to the activation of IL-6 gene in HTLV-I-infected cells, we first studied the regulatory regions in the IL-6 gene transcription by transfection of chloramphenicol acetyltransferase (CAT) reporter plasmids containing the IL-6 promoter. When transfected into HTLV-I-infected T-cell lines MT-2 and HUT-102, IL-6 promoter/CAT plasmids were strongly activated without any stimulation. By deletion analysis of 52 upstream region of IL-6 promoter, the DNA region between -73 and -59 bp from the transcription start site of IL-6 gene was important in the expression of IL-6/CAT activities in HTLV-I-infected cells. This region contains nuclear factor (NF)-kappa B binding site. The site-directed mutation of the kappa B motif in IL-6/CAT plasmid resulted in the complete abrogation of IL-6 promoter activity in these cells. Furthermore, when IL-6 promoter/CAT plasmid was introduced into an HTLV-I-uninfected T- cell line, Jurkat, IL-6 promoter activity was silent in the basal level, but strongly increased by the cotransfection with an HTLV-I tax expression plasmid. However, tax expression plasmid showed no transactivation activity, when kappa B site was mutated in IL-6 promoter/CAT plasmid. We found that the IL-6 kappa B site specifically formed a complex with NF-kappa B-containing nuclear extracts from MT-2 and HUT-102 cells. Finally, transfection of HTLV-I tax into Jurkat cells resulted in induction of specific binding of nuclear extracts to the NF-kappa B sequence. These results strongly suggest that HTLV-I tax gene may transactivate IL-6 gene through kappa B site in HTLV-I- positive T-cell lines and activation of NF-kappa B may be crucial in HTLV-I-induced IL-6 gene activation in ATL.

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