All-Trans Retinoic Acid Can Reduce Proviral DNA of Human T-Cell Leukemia Virus as a Reverse Transcriptase Inhibitor.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4623-4623
Author(s):  
Terufumi Yamaguchi ◽  
Yasuhiro Maeda ◽  
Satomi Ueda ◽  
Yasuki Hijikata ◽  
Mitsuhiro Matsuda ◽  
...  
Keyword(s):  
T Cell ◽  
Reverse Transcriptase ◽  
Cell Lines ◽  
Reverse Transcriptase Activity ◽  
Cell Leukemia ◽  
Proviral Dna ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
T Cell Lines ◽  
Hiv 1

Abstract We previously reported that all-trans retinoic acid (ATRA) inhibits growth in HTLV-1-positive T-cell lines and fresh cells from patients with adult T-cell leukemia. However, the mechanism of this inhibition is not clear. In the present study, we observed the NF-κB transcriptional activity as well as cell growth in HTLV-1-positive T-cell lines decreased significantly in these cells in the presence of ATRA. However, no significant growth inhibition was observed after treatment with IFN-γ, TNF-α, and TGF-β of growth inhibitory cytokines induced by ATRA. Thereafter, we observed that ATRA reduced HTLV-1 proviral DNA, gag and tax mRNA load using a real time quantitative polymerase chain reaction and soluble IL-2 receptor in the culture supernatant using ELISA in HTLV-1-positive T-cell lines. Interestingly, ATRA significantly inhibited reverse transcriptase activity similar to azidothymidine in HTLV-1-positive T-cell lines. These results suggested that ATRA could inhibit reverse transcriptase activity in the growth inhibition of ATL cells. Additionally, an effect of ATRA on replication of the human immunodeficiency virus (HIV) was also observed. ATRA significantly reduced the HIV proviral DNA load of both a HIV-1-positive cell line and HIV-1-infected patients. These results indicated that ATRA may be useful for HIV treatment in a clinical setting.

Dichotomy of All-Trans Retinoic Acid Inducing Signals for Adult T-Cell Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4803-4803
Author(s):  
Yasuhiro Maeda ◽  
Terufumi Yamaguchi ◽  
Yasuki Hijikata ◽  
Yasuyoshi Morita ◽  
Chikara Hirase ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
T Cell ◽  
Cell Lines ◽  
Transcriptional Activity ◽  
Cell Leukemia ◽  
Proviral Dna ◽  
Adult T Cell Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
T Cell Lines

Abstract We previously reported that all-trans retinoic acid (ATRA) inhibits growth in HTLV-1-positive T-cell lines and fresh cells from patients with adult T-cell leukemia. However, the mechanism of this inhibition is not clear. In the present study, we observed that NF-κB transcriptional activity as well as cell growth decreased significantly in HTLV-1-positive T-cell lines in the presence of ATRA. Furthermore, we observed that ATRA reduced HTLV-1 proviral DNA, HTLV-1 genes (gag, tax or pol mRNA) using the real time quantitative polymerase chain reaction. SIL-2R was reduced by ATRA in both protein level (culture supernantant) and mRNA level in HTLV-1-positive T-cell lines. Interestingly, ATRA significantly inhibited RT activity similar to azidothimidine (AZT) in HTLV-1-positive T-cell lines. Moreover, AZT was inhibitory of proviral DNA but not NF-kB transcriptional activity and sIL-2R on HTLV-1, however ATRA was inhibitory of NF-kB, proviral DNA and sIL-2R on HTLV-1. These results suggested that the decrease of sIL-2R induced by ATRA may be caused by the actions of a NF-kB inhibitor acting on the NF-kB/sIL-2R signal pathway. These results suggested that ATRA could have two roles, as a NF-kB inhibitor and as a RT inhibitor.

Clinical Efficacy of ATRA for Adult T-Cell Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4985-4985
Author(s):  
Yasuhiro Maeda ◽  
Terufumi Yamaguchi ◽  
Chikara Hirase ◽  
Akihisa Kanamaru
Keyword(s):  
T Cell ◽  
Clinical Effects ◽  
T Cell Leukemia ◽  
Skin Involvement ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Major Toxicity ◽  
T Cell Lines

Abstract We previously reported that all-trans retinoic acid (ATRA) inhibited growth in HTLV-I- positive T-cell lines and fresh cells from patients with adult T-cell leukemia. We here confirmed the clinical effects of ATRA in 20 patients with ATL. Twenty patients (n=20) with median age of 56 years (range 35–68 years) diagnosed with ATL received ATRA orally. ATRA was administered for a median of 25.7 days (range 14–56 days). Efficacy was described below; no CR case, PR case was 55%, NR case was 45%. In 7 acute cases, PR case was 4 (20%) and NR case was 3 (15%). In 3 lymphoma cases, no NR case and 3 PR cases (15%) was found. In 4 chronic cases, PR case was 1 (4%) and NR case was 3 (15%). In 6 skin type. PR case was 3 (15 %) and NR case was 3 (15%). Major side effects were headache (n=5), transient liver dysfunction (n=2), hyperlipidemia (n=2) and anorexia (n=1). No major toxicity was observed. These results indicated that ATRA might be a useful agent for skin involvement of ATL with safety.

Cell-Surface Heparan Sulfate Proteoglycan Mediates HIV-1 Infection of T-Cell Lines

1993 ◽  
Vol 9 (2) ◽  
pp. 167-174 ◽  
Author(s):  
MAHESH PATEL ◽  
MASAKI YANAGISHITA ◽  
GREGORY RODERIQUEZ ◽  
DUMITH CHEQUER BOU-HABIB ◽  
TAMAS ORAVECZ ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Surface ◽  
Heparan Sulfate ◽  
Cell Lines ◽  
Heparan Sulfate Proteoglycan ◽  
Sulfate Proteoglycan ◽  
T Cell Lines ◽  
Hiv 1

Frequent expression of interleukin-9 mRNA and infrequent involvement of interleukin-9 in proliferation of primary adult T-cell leukemia cells and HTLV-I infected T-cell lines

1997 ◽  
Vol 21 (3) ◽  
pp. 211-216 ◽  
Author(s):  
Kakushi Matsushita ◽  
Naomichi Arima ◽  
Hideo Ohtsubo ◽  
Hiroshi Fujiwara ◽  
Shiroh Hidaka ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lines ◽  
Leukemia Cells ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
T Cell Lines ◽  
Interleukin 9

Clinical efficacy of all-trans retinoic acid for treating adult T cell leukemia

2007 ◽  
Vol 134 (6) ◽  
pp. 673-677 ◽  
Author(s):  
Yasuhiro Maeda ◽  
Terufumi Yamaguchi ◽  
Yasuki Hijikata ◽  
Miyako Tanaka ◽  
Chikara Hirase ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
T Cell ◽  
Clinical Efficacy ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Suppression of Cell Growth and Induction of Apoptosis of HTLV-I-Infected T-Cell Lines and Primary ATL Cells by Galectin-9.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4810-4810
Author(s):  
Taeko Okudaira ◽  
Mariko Tomita ◽  
Mitsuomi Hirashima ◽  
Naoki Mori
Keyword(s):  
T Cell ◽  
Cell Growth ◽  
Cell Lines ◽  
Cyclin B1 ◽  
Type I ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Galectin 3 ◽  
T Cell Lines

Abstract Adult T-cell leukemia (ATL) is a fatal malignancy of T lymphocytes caused by infection with human T-cell leukemia virus type I (HTLV-I), and remains incurable. Therefore, novel treatments are urgently needed. Galectins are a family of animal lectins with diverse biological activities. They function both extracellularly, by interacting with cell-surface and extracellular matrix glycoproteins and glycolipids, and intracellularly, by interacting with cytoplasmic and nuclear proteins to modulate signaling pathways. The distribution of galectins is quite diverse, and their expression in various leukocytes has been observed. To determine whether expression of galectins in T cells correlates with HTLV-I infection, we surveyed a number of uninfected and HTLV-I-infected T-cell lines for galectin-3, -8, and -9 expression by RT-PCR. Expression of galectin-8 did not correlate with HTLV-I infection. Galectin-3 was abundantly expressed in HTLV-I-infected T-cell lines and primary ATL cells, but not in uninfected T-cell lines. In contrast, galectin-9 was abundantly expressed in uninfected T-cell lines and normal PBMCs, but not in HTLV-I-infected T-cell lines and primary ATL cells. HTLV-I transformed protein, Tax, did not affect the expression of galectin-3 and -9. It was previously shown that galectin-8 and -9 are proapoptotic proteins. We found that galectin-9 prevented cell growth of HTLV-I-infected T-cell lines and primary ATL cells compared with galectin-8. Galectin-9 induced cell cycle arrest by reducing the expression of cyclin D1, cyclin D2, cyclin B1, Cdk1, Cdk4, Cdk6, and Cdc25C, and apoptosis by reducing the expression of XIAP and c-IAP2. Most of these genes are known to be regulated by NF-κB, which plays a critical role in oncogenesis by HTLV-I. Galectin-9 suppressed phosphorylation of IκBα. Most importantly, treatment with galectin-9 reduced tumor formation from an HTLV-I-infected T-cell line, HUT-102, when these cells were inoculated s.c. into severe combined immunodeficient mice. Our results suggest that galectin-9 may be a new approach for management of ATL.

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

Blood ◽  
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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