Establishment and characterization of T-cell lines (yana-I and yana-II) derived from a patient with chronic adult T-cell leukemia (ATL).

Abstract Adult T-cell leukemia (ATL) is caused by human T-cell leukemia virus type I (HTLV-I) and remains incurable. Retinoid is a collective term for compounds, which bind to and activate retinoic acid receptors (RARα, β, γ and RXRα, β, γ), members of nuclear hormone receptor superfamily. It is involved in cell differentiation, morphogenesis, proliferation, and anti-neoplastic processes. The most important endogenous retinoid is all-trans-retinoic acid (ATRA), which is an RARα, β, and γ ligand. ATRA and its mimics have been in clinical use for treatment of acute promyelocytic leukemia (APL) and adult T-cell leukemia (ATL). Many synthetic retinoids have been developed and attempts to improve their medicinal properties have been made. Among them, a novel synthetic retinoid, Am80 (Tamibarotene) is an RARα- and RARβ-specific (but RARγ- and RXRs-nonbinding) synthetic retinoid that is expected to overcome ATRA resistance, because of several times more potent differentiation activity than ATRA and sustained plasma level during continuous administration due to a lower affinity for cellular retinoic acid binding protein. On this background, we examined the inhibitory effect of Am80 on HTLV-I-infected T-cell lines and primary ATL cells. Am80 showed little growth inhibition of peripheral blood mononuclear cells, but it markedly inhibited the growth of both HTLV-I-infected T-cell lines and primary ATL cells. Am 80 could arrest cells in the G1 phase of the cell cycle and induced apoptosis in HTLV-I-infected T-cell lines. The NF-κB pathway is critical for the immortalization and survival of HTLV-I-infected T cells. Therefore, NF-κB pathway was examined as potential targets of Am80 signaling. Am80 significantly inhibited phosphorylation of IκBα and NF-κB-DNA binding, in conjunction with the reduction of expression of proteins involved in the G1-S cell cycle transition and apoptosis. Furthermore, in animal studies, treatment with Am80 produced partial inhibition of growth of tumors of an HTLV-I-infected T-cell line transplanted subcutaneously in severe combined immunodeficient mice. These findings clearly demonstrate that Am80 is a potential inhibitor of NF-κB in ATL cells, and might be a useful therapeutic agent against ATL.

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Apoptosis Induced by the Histone Deacetylase Inhibitor FR901228 in Human T-Cell Leukemia Virus Type 1-Infected T-Cell Lines and Primary Adult T-Cell Leukemia Cells

Journal of Virology ◽

10.1128/jvi.78.9.4582-4590.2004 ◽

2004 ◽

Vol 78 (9) ◽

pp. 4582-4590 ◽

Cited By ~ 39

Author(s):

Naoki Mori ◽

Takehiro Matsuda ◽

Masayuki Tadano ◽

Takao Kinjo ◽

Yasuaki Yamada ◽

...

Keyword(s):

T Cell ◽

Cell Lines ◽

Leukemia Virus ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Adult T Cell Leukemia ◽

Human T Cell ◽

Induced Apoptosis ◽

T Cell Lines

ABSTRACT Inhibition of histone deacetylase (HDAC) activity induces growth arrest, differentiation, and, in certain cell types, apoptosis. FR901228, FK228, or depsipeptide, is an HDAC inhibitor effective in T-cell lymphomas. Adult T-cell leukemia (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1) and remains incurable. We examined whether FR901228 is effective for treatment of ATL by assessing its ability to induce apoptosis of HTLV-1-infected T-cell lines and primary leukemic cells from ATL patients. FR901228 induced apoptosis of Tax-expressing and -unexpressing HTLV-1-infected T-cell lines and selective apoptosis of primary ATL cells, especially those of patients with acute ATL. FR901228 also efficiently reduced the DNA binding of NF-κB and AP-1 in HTLV-1-infected T-cell lines and primary ATL cells and down-regulated the expression of Bcl-xL and cyclin D2, regulated by NF-κB. Although the viral protein Tax is an activator of NF-κB and AP-1, FR901228-induced apoptosis was not associated with reduced expression of Tax. In vivo use of FR901228 partly inhibited the growth of tumors of HTLV-1-infected T cells transplanted subcutaneously in SCID mice. Our results indicated that FR901228 could induce apoptosis of these cells and suppress the expression of NF-κB and AP-1 and suggest that FR901228 could be therapeutically effective in ATL.

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Bay 11-7082 inhibits transcription factor NF-kappa B and induces apoptosis of HTLV-I-infected T-cell lines and primary adult T-cell leukemia cells

Blood ◽

10.1182/blood-2002-01-0151 ◽

2002 ◽

Vol 100 (5) ◽

pp. 1828-1834 ◽

Cited By ~ 197

Author(s):

N. Mori

Keyword(s):

Transcription Factor ◽

T Cell ◽

Cell Lines ◽

Leukemia Cells ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Nf Kappa B ◽

Adult T Cell Leukemia ◽

T Cell Lines

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Failure of regulation of Tac antigen/TCGF receptor on adult T-cell leukemia cells by anti-Tac monoclonal antibody

Blood ◽

10.1182/blood.v61.5.1014.bloodjournal6151014 ◽

1983 ◽

Vol 61 (5) ◽

pp. 1014-1016

Author(s):

M Tsudo ◽

T Uchiyama ◽

H Uchino ◽

J Yodoi

Keyword(s):

Monoclonal Antibody ◽

T Cells ◽

T Cell ◽

Cell Lines ◽

Leukemic Cells ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Down Regulation ◽

Adult T Cell Leukemia ◽

T Cell Lines

Anti-Tac monoclonal antibody, which blocks the membrane binding and action of human T-cell growth factor (TCGF), is strongly proposed to recognize TCGF receptor. We have demonstrated that anti-Tac antibody reacted with leukemic cells from patients with adult T-cell leukemia (ATL) and reacted with T-cell lines established from ATL cells. Although antigenic modulation, or down-regulation, of Tac antigen on activated normal T cells was induced by anti-Tac antibody, the expression of Tac antigen on ATL cells or T-cell lines was not affected when examined by the fluorescence-activated cell sorter (FACS) and the radioassay using 125I-staphylococcal protein A. These results indicate that regulation of Tac antigen-TCGF receptor is different between normal and malignant T cells, suggesting that failure of down- regulation of Tac antigen on leukemic cells by anti-Tac antibody may play an important role in the malignant proliferation of ATL cells.

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Cells of adult T-cell leukemia evade HTLV-1 Tax/NF-κB hyperactivation–induced senescence

Blood Advances ◽

10.1182/bloodadvances.2018029322 ◽

2019 ◽

Vol 3 (4) ◽

pp. 564-569 ◽

Cited By ~ 6

Author(s):

Abigail M. Druck Shudofsky ◽

Chou-Zen Giam

Keyword(s):

T Cell ◽

Cell Lines ◽

Leukemia Virus ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Altered Expression ◽

Adult T Cell Leukemia ◽

Human T Cell ◽

T Cell Lines

Abstract Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATL). The HTLV-1 viral trans-activator/oncoprotein Tax is a major driver of ATL, yet it induces rapid p21Cip1/Waf1 (p21)- and p27Kip1-mediated cellular senescence through constitutive activation (hyperactivation) of NF-κB. Although constitutive NF-κB activation is a common feature of T/B-cell leukemia/lymphoma, including ATL, it is not known how ATL cells maintain chronic NF-κB activation without undergoing senescence. Here, we demonstrate that, in contrast to HTLV-1− T-cell lines, ATL cell lines no longer undergo Tax-induced senescence. Although Tax+ and Tax− ATL cell lines showed signatures of constitutive NF-κB activation, their ability to progress through the cell cycle was unaffected. In some cases, ATL cell lines continued to proliferate despite significant upregulation of p21; additionally, many cell lines displayed altered expression of G1 and G1/S cyclins, particularly overexpression of cyclin D2. We propose that, during the course of ATL development, leukemia cells acquire genetic/epigenetic changes that can mitigate the senescence response triggered by NF-κB hyperactivation. Restoring the NF-κB–induced senescence response would likely help to control the development and progression of ATL and similar lymphoid malignancies.

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Overexpression of caveolin-1 in adult T-cell leukemia

Blood ◽

10.1182/blood-2009-08-240044 ◽

2010 ◽

Vol 115 (11) ◽

pp. 2220-2230 ◽

Cited By ~ 6

Author(s):

Shigeki Sawada ◽

Chie Ishikawa ◽

Hiroe Tanji ◽

Sawako Nakachi ◽

Masachika Senba ◽

...

Keyword(s):

T Cell ◽

Cell Line ◽

Cell Lines ◽

Signal Pathways ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Caveolin 1 ◽

Adult T Cell Leukemia ◽

Human T Cell ◽

T Cell Lines

AbstractCaveolin-1 is implicated in the regulation of signal pathways. Adult T-cell leukemia (ATL) is a T-cell malignancy causatively associated with human T-cell leukemia virus type 1 (HTLV-1). To determine the role of caveolin-1 in leukemogenesis, we examined caveolin-1 expression levels in HTLV-1–infected T-cell lines and ATL cells. These cells expressed high levels of caveolin-1 compared with uninfected T-cell lines and normal peripheral blood mononuclear cells (PBMCs). Caveolin-1–positive ATL cells were detected in ATL lymph nodes and skin lesions, and caveolin-1 was also detected in the plasma of patients with ATL. Infection of a human T-cell line, an epithelial cell line, and normal PBMCs with HTLV-1 induced caveolin-1 expression. The viral protein Tax transcriptionally activated caveolin-1 gene through nuclear factor-κB and cAMP response element binding protein signal pathways. HTLV-1–infected T-cell lines, and ATL cells are known to be resistant to transforming growth factor β (TGF-β)–induced growth inhibition. Caveolin-1 was colocalized with TGF-β type I receptor in HTLV-1–infected T-cell lines and suppressed TGF-β signaling. Caveolin-1 knockdown in an HTLV-1–infected T-cell line exhibited susceptibility to TGF-β. Thus, we describe a new function for Tax, repression of TGF-β signaling through caveolin-1 expression, which may play a critical role in ATL leukemogenesis.

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