scholarly journals Critical Role for TSLC1 Expression in the Growth and Organ Infiltration of Adult T-Cell Leukemia Cells In Vivo

2008 ◽  
Vol 82 (23) ◽  
pp. 11958-11963 ◽  
Author(s):  
M. Zahidunnabi Dewan ◽  
Naofumi Takamatsu ◽  
Tomonori Hidaka ◽  
Kinta Hatakeyama ◽  
Shingo Nakahata ◽  
...  
Keyword(s):  
T Cell ◽  
Critical Role ◽  
Leukemia Cell ◽  
Tumor Formation ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Human T Cell

ABSTRACT Adult T-cell leukemia (ATL) is associated with human T-cell leukemia virus type 1 infection. The tumor suppressor lung cancer 1 (TSLC1) gene was previously identified as a novel cell surface marker for ATL, and this study demonstrated the involvement of TSLC1 expression in tumor growth and organ infiltration of ATL cells. In experiments using NOD/SCID/γcnull mice, both leukemia cell lines and primary ATL cells with high TSLC1 expression caused more tumor formation and aggressive infiltration of various organs of mice. Our results suggest that TSLC1 expression in ATL cells plays an important role in the growth and organ infiltration of ATL cells.

scholarly journals 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

2000 ◽  
Vol 74 (20) ◽  
pp. 9610-9616 ◽  
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.

scholarly journals Oncogenic mutations in the FBXW7 gene of adult T-cell leukemia patients

2016 ◽  
Vol 113 (24) ◽  
pp. 6731-6736 ◽  
Author(s):  
Chien-Hung Yeh ◽  
Marcia Bellon ◽  
Joanna Pancewicz-Wojtkiewicz ◽  
Christophe Nicot
Keyword(s):  
T Cell ◽  
Tumor Suppressor ◽  
Tumor Formation ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Notch1 Signaling ◽  
Dismal Prognosis ◽  
Human T Cell

Human T-cell leukemia virus type 1 (HTLV-I) is associated with adult T-cell leukemia (ATL), an aggressive lymphoproliferative disease with a dismal prognosis. We have previously described the presence of Notch1 activating mutations and constitutive Notch1 signaling in patients with acute ATL. In this study, we report a high frequency of F-box and WD repeat domain containing 7 (FBXW7)/hCDC4 mutations within the WD40 substrate-binding domain in 8 of 32 acute ATL patients (25%). Functionally, ATL FBXW7 mutants lost their ability to interact with intracellular Notch (NICD), resulting in increased protein stability and constitutive Notch1 signaling. Consistent with the loss-of-function found in ATL patients, expression of WT FBXW7 in several patient-derived ATL lines demonstrated strong tumor-suppressor activity characterized by reduced proliferation of ATL cells. Remarkably, two FBXW7 mutants, D510E and D527G, demonstrated oncogenic activity when expressed in the presence of HTLV-I Tax, mutated p53 R276H, or c-Myc F138C found in human cancers. Transforming activity was further demonstrated by the ability of the FBXW7 D510E mutant to provide IL-2–independent growth of Tax-immortalized human T cells and increase the tumor formation in a xenograft mouse model of ATL. This study suggests that FBXW7, normally a tumor suppressor, can act as an oncogene when mutated and may play an important role in the pathogenesis of ATL.

scholarly journals Long Noncoding RNA ANRIL Supports Proliferation of Adult T-Cell Leukemia Cells through Cooperation with EZH2

2018 ◽  
Vol 92 (24) ◽  
Author(s):  
Zaowen Song ◽  
Wencai Wu ◽  
Mengyun Chen ◽  
Wenzhao Cheng ◽  
Juntao Yu ◽  
...  
Keyword(s):  
T Cell ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Human T Cell

ABSTRACT Adult T-cell leukemia (ATL) is a highly aggressive T-cell malignancy induced by human T-cell leukemia virus type 1 (HTLV-1) infection. Long noncoding RNA (lncRNA) plays a critical role in the development and progression of multiple human cancers. However, the function of lncRNA in HTLV-1-induced oncogenesis has not been elucidated. In the present study, we show that the expression level of the lncRNA ANRIL was elevated in HTLV-1-infected cell lines and clinical ATL samples. E2F1 induced ANRIL transcription by enhancing its promoter activity. Knockdown of ANRIL in ATL cells repressed cellular proliferation and increased apoptosis in vitro and in vivo. As a mechanism for these actions, we found that ANRIL targeted EZH2 and activated the NF-κB pathway in ATL cells. This activation was independent of the histone methyltransferase (HMT) activity of EZH2 but required the formation of an ANRIL/EZH2/p65 ternary complex. A chromatin immunoprecipitation assay revealed that ANRIL/EZH2 enhanced p65 DNA binding capability. In addition, we observed that the ANRIL/EZH2 complex repressed p21/CDKN1A transcription through H3K27 trimethylation of the p21/CDKN1A promoter. Taken together, our results implicate that the lncRNA ANRIL, by cooperating with EZH2, supports the proliferation of HTLV-1-infected cells, which is thought to be critical for oncogenesis.IMPORTANCE Human T-cell leukemia virus type 1 (HTLV-1) is the pathogen that causes adult T-cell leukemia (ATL), which is a unique malignancy of CD4+ T cells. A role for long noncoding RNA (lncRNA) in HTLV-1-mediated cellular transformation has not been described. In this study, we demonstrated that the lncRNA ANRIL was important for maintaining the proliferation of ATL cells in vitro and in vivo. ANRIL was shown to activate NF-κB signaling through forming a ternary complex with EZH2 and p65. Furthermore, epigenetic inactivation of p21/CDKN1A was involved in the oncogenic function of ANRIL. To the best of our knowledge, this is the first study to address the regulatory role of the lncRNA ANRIL in ATL and provides an important clue to prevent or treat HTLV-1-associated human diseases.

scholarly journals Induction of Adult T-Cell Leukemia-Like Lymphoproliferative Disease and Its Inhibition by Adoptive Immunotherapy in T-Cell-Deficient Nude Rats Inoculated with Syngeneic Human T-Cell Leukemia Virus Type 1-Immortalized Cells

1999 ◽  
Vol 73 (7) ◽  
pp. 6031-6040 ◽  
Author(s):  
Takashi Ohashi ◽  
Shino Hanabuchi ◽  
Hirotomo Kato ◽  
Yoshihiro Koya ◽  
Fumiyo Takemura ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lines ◽  
Leukemia Virus ◽  
Tumor Development ◽  
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) has been shown to be the etiologic agent of adult T-cell leukemia (ATL), but the in vivo mechanism by which the virus causes the malignant transformation is largely unknown. In order to investigate the mechanisms of HTLV-1 leukemogenesis, we developed a rat model system in which ATL-like disease was reproducibly observed, following inoculation of various rat HTLV-1-immortalized cell lines. When previously established cell lines, F344-S1 and TARS-1, but not TART-1 or W7TM-1, were inoculated, systemic multiple tumor development was observed in adult nude (nu/nu) rats. FPM1 cells, newly established from a heterozygous (nu/+) rat syngeneic to nu/nurats, caused transient tumors only at the injection site in adult nu/nu rats, but could progressively grow in newborn nu/nu rats and metastasize in lymph nodes. The derivative cell line (FPM1-V1AX) serially passed through newbornnu/nu rats acquired the potency to grow in adultnu/nu rats. These results indicated that only some with additional changes but not all of the in vitro HTLV-1-immortalized cell lines possessed in vivo tumorigenicity. Using the syngeneic system, we further showed the inhibition of tumor development by transferring splenic T cells from immunized rats, suggesting the involvement of T cells in the regression of tumors. This novel and reproducible nude rat model of human ATL would be useful for investigation of leukemogenesis and antitumor immune responses in HTLV-1 infection.

scholarly journals Long noncoding RNA ANRIL supports proliferation of adult T-cell leukemia cells through cooperation with EZH2

2018 ◽  
Author(s):  
Zaowen Song ◽  
Wencai Wu ◽  
Mengyun Chen ◽  
Wenzhao Cheng ◽  
Juntao Yu ◽  
...  
Keyword(s):  
T Cell ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Human T Cell

ABSTRACTAdult T-cell leukemia (ATL) is a highly aggressive T-cell malignancy induced by human T-cell leukemia virus type 1 (HTLV-1) infection. Long noncoding RNA (lncRNA) plays a critical role in the development and progression of multiple human cancers. However, the function of lncRNA on HTLV-1-induced oncogenesis has not been elucidated. In the present study, we show that the expression of the lncRNA ANRIL was elevated in HTLV-1 infected cell lines and clinical ATL samples. E2F1 induced ANRIL transcription by enhancing its promoter activity. Knocking down of ANRIL in ATL cells repressed cellular proliferation and increased apoptosis in vitro and in vivo. As a mechanism for these actions, we found that ANRIL targeted EZH2, and activated the NF-κB pathway in ATL cells. This activation was independent of the histone methyltransferase (HMT) activity of EZH2, but required the formation of an ANRIL/EZH2/p65 ternary complex. Chromatin immunoprecipitation assay revealed that ANRIL/EZH2 enhanced p65 DNA binding capability. In addition, we observed that ANRIL/EZH2 complex repressed p21/CDKN1A transcription through H3K27 trimethylation of the p21/CDKN1A promoter. Taken together, our results implicate that lncRNA ANRIL, by cooperating with EZH2, supports the proliferation of HTLV-1 infected cells, which is thought to be critical for oncogenesis.IMPORTANCEHuman T-cell leukemia virus type 1 (HTLV-1) is the pathogen that causes adult T-cell leukemia (ATL), which is a unique malignancy of CD4+ T cells. A role for long noncoding RNA (lncRNA) in HTLV-1-mediated cellular transformation has not been described. In this study, we demonstrated that lncRNA ANRIL was important for maintaining proliferation of ATL cells in vitro and in vivo. ANRIL was shown to activate NF-κB signaling through forming a ternary complex with EZH2 and p65. Further, epigenetic inactivation of p21/CDKN1A was involved in the oncogenic function of ANRIL. To the best of our knowledge, this is the first study to address the regulatory role of the lncRNA ANRIL in ATL and provides an important clue to prevent or treat HTLV-1 associated human diseases.

scholarly journals T3 surface molecules on adult T cell leukemia cells are modulated in vivo

Blood ◽  
1986 ◽  
Vol 67 (4) ◽  
pp. 1070-1076
Author(s):  
M Matsuoka ◽  
T Hattori ◽  
T Chosa ◽  
H Tsuda ◽  
S Kuwata ◽  
...  
Keyword(s):  
T Cell ◽  
Type I ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Receptor Complexes ◽  
Human T Cell

Cells from eight patients with adult T cell leukemia (ATL) and from four patients with non-ATL were examined to see if the T3 antigen of these cells could be modulated in vitro. We found a low density of T3 antigen and the presence of Tac antigen on cells from all patients with ATL. The density of T3 antigen on non-ATL cells was normal, and Tac antigen was not detected. Modulation of T3 antigen and an increase in Tac antigen-positive cells occurred when cells from patients with T4 non-ATL were cultured with OKT3 monoclonal antibody (mAb). Those changes in T3 antigen density and the appearance of Tac antigen-bearing cells by OKT3 mAb were not so marked when ATL cells were used. But the modulation of T3 antigen and the increase in Tac antigen-bearing cells by OKT3 mAb were closely related in cells from six ATL patients. These findings suggest that T3 T cell antigen receptor complexes on ATL cells are not functionally “frozen” by leukemic changes and might be modulated in vivo. In addition, modulation of T3 surface antigen on ATL cells was not induced by cultivation with human T cell leukemia virus type I particles and envelope proteins obtained by gene technology.

scholarly journals T3 surface molecules on adult T cell leukemia cells are modulated in vivo

Blood ◽  
1986 ◽  
Vol 67 (4) ◽  
pp. 1070-1076 ◽  
Author(s):  
M Matsuoka ◽  
T Hattori ◽  
T Chosa ◽  
H Tsuda ◽  
S Kuwata ◽  
...  
Keyword(s):  
T Cell ◽  
Type I ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Receptor Complexes ◽  
Human T Cell

Abstract Cells from eight patients with adult T cell leukemia (ATL) and from four patients with non-ATL were examined to see if the T3 antigen of these cells could be modulated in vitro. We found a low density of T3 antigen and the presence of Tac antigen on cells from all patients with ATL. The density of T3 antigen on non-ATL cells was normal, and Tac antigen was not detected. Modulation of T3 antigen and an increase in Tac antigen-positive cells occurred when cells from patients with T4 non-ATL were cultured with OKT3 monoclonal antibody (mAb). Those changes in T3 antigen density and the appearance of Tac antigen-bearing cells by OKT3 mAb were not so marked when ATL cells were used. But the modulation of T3 antigen and the increase in Tac antigen-bearing cells by OKT3 mAb were closely related in cells from six ATL patients. These findings suggest that T3 T cell antigen receptor complexes on ATL cells are not functionally “frozen” by leukemic changes and might be modulated in vivo. In addition, modulation of T3 surface antigen on ATL cells was not induced by cultivation with human T cell leukemia virus type I particles and envelope proteins obtained by gene technology.

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