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 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.

scholarly journals Biochemical Characterization, Specificity and Inhibition Studies of HTLV-1, HTLV-2, and HTLV-3 Proteases

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 127
Author(s):  
Norbert Kassay ◽  
János András Mótyán ◽  
Krisztina Matúz ◽  
Mária Golda ◽  
József Tőzsér
Keyword(s):  
T Cell ◽  
Biochemical Characterization ◽  
Leukemia Virus ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Human T Cell ◽  
T Cell Leukemia Virus

The human T-lymphotropic viruses (HTLVs) are causative agents of severe diseases including adult T-cell leukemia. Similar to human immunodeficiency viruses (HIVs), the viral protease (PR) plays a crucial role in the viral life-cycle via the processing of the viral polyproteins. Thus, it is a potential target of anti-retroviral therapies. In this study, we performed in vitro comparative analysis of human T-cell leukemia virus type 1, 2, and 3 (HTLV-1, -2, and -3) proteases. Amino acid preferences of S4 to S1′ subsites were studied by using a series of synthetic oligopeptide substrates representing the natural and modified cleavage site sequences of the proteases. Biochemical characteristics of the different PRs were also determined, including catalytic efficiencies and dependence of activity on pH, temperature, and ionic strength. We investigated the effects of different HIV-1 PR inhibitors (atazanavir, darunavir, DMP-323, indinavir, ritonavir, and saquinavir) on enzyme activities, and inhibitory potentials of IB-268 and IB-269 inhibitors that were previously designed against HTLV-1 PR. Comparative biochemical analysis of HTLV-1, -2, and -3 PRs may help understand the characteristic similarities and differences between these enzymes in order to estimate the potential of the appearance of drug-resistance against specific HTLV-1 PR inhibitors.

scholarly journals Tax and Overlapping Rex Sequences Do Not Confer the Distinct Transformation Tropisms of Human T-Cell Leukemia Virus Types 1 and 2

2003 ◽  
Vol 77 (14) ◽  
pp. 7728-7735 ◽  
Author(s):  
Jianxin Ye ◽  
Li Xie ◽  
Patrick L. Green
Keyword(s):  
T Cells ◽  
T Cell ◽  
Leukemia Virus ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
T Cell Leukemia Virus

ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 are distinct oncogenic retroviruses that infect several cell types but display their biological and pathogenic activity only in T cells. Previous studies have indicated that in vivo HTLV-1 has a preferential tropism for CD4+ T cells, whereas HTLV-2 in vivo tropism is less clear but appears to favor CD8+ T cells. Both CD4+ and CD8+ T cells are susceptible to HTLV-1 and HTLV-2 infection in vitro, and HTLV-1 has a preferential immortalization and transformation tropism of CD4+ T cells, whereas HTLV-2 immortalizes and transforms primarily CD8+ T cells. The molecular mechanism that determines this tropism of HTLV-1 and HTLV-2 has not been determined. HTLV-1 and HTLV-2 carry the tax and rex transregulatory genes in separate but partially overlapping reading frames. Since Tax has been shown to be critical for cellular transformation in vitro and interacts with numerous cellular processes, we hypothesized that the viral determinant of transformation tropism is encoded by tax. Using molecular clones of HTLV-1 (Ach) and HTLV-2 (pH6neo), we constructed recombinants in which tax and overlapping rex genes of the two viruses were exchanged. p19 Gag expression from proviral clones transfected into 293T cells indicated that both recombinants contained functional Tax and Rex but with significantly altered activity compared to the wild-type clones. Stable transfectants expressing recombinant viruses were established, irradiated, and cocultured with peripheral blood mononuclear cells. Both recombinants were competent to transform T lymphocytes with an efficiency similar to that of the parental viruses. Flow cytometry analysis indicated that HTLV-1 and HTLV-1/TR2 had a preferential tropism for CD4+ T cells and that HTLV-2 and HTLV-2/TR1 had a preferential tropism for CD8+ T cells. Our results indicate that tax/rex in different genetic backgrounds display altered functional activity but ultimately do not contribute to the different in vitro transformation tropisms. This first study with recombinants between HTLV-1 and HTLV-2 is the initial step in elucidating the different pathobiologies of HTLV-1 and HTLV-2.

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 Comparison of the Genetic Organization, Expression Strategies and Oncogenic Potential of HTLV-1 and HTLV-2

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Francesca Rende ◽  
Ilaria Cavallari ◽  
Maria Grazia Romanelli ◽  
Erica Diani ◽  
Umberto Bertazzoni ◽  
...  
Keyword(s):  
T Cell ◽  
Leukemia Virus ◽  
Spastic Paraparesis ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Pathogenic Potential ◽  
Adult T Cell Leukemia ◽  
Human T Cell

Human T cell leukemia virus types 1 and 2 (HTLV-1 and HTLV-2) are genetically related complex retroviruses that are capable of immortalizing human T-cells in vitro and establish life-long persistent infections in vivo. In spite of these apparent similarities, HTLV-1 and HTLV-2 exhibit a significantly different pathogenic potential. HTLV-1 is recognized as the causative agent of adult T-cell leukemia/lymphoma (ATLL) and tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). In contrast, HTLV-2 has not been causally linked to human malignancy, although it may increase the risk of developing inflammatory neuropathies and infectious diseases. The present paper is focused on the studies aimed at defining the viral genetic determinants of the pathobiology of HTLV-1 and HTLV-2 through a comparison of the expression strategies and functional properties of the different gene products of the two viruses.

scholarly journals Human T-Cell Leukemia Virus Type 1 Tax Oncoprotein Suppression of Multilineage Hematopoiesis of CD34+ Cells In Vitro

2003 ◽  
Vol 77 (22) ◽  
pp. 12152-12164 ◽  
Author(s):  
Adam Tripp ◽  
Yingxian Liu ◽  
Michelle Sieburg ◽  
Joanne Montalbano ◽  
Stephen Wrzesinski ◽  
...  
Keyword(s):  
T Cell ◽  
Leukemia Virus ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Hematopoietic Progenitor ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
T Cell Lines

ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 are highly related viruses that differ in disease manifestation. HTLV-1 is the etiologic agent of adult T-cell leukemia and lymphoma, an aggressive clonal malignancy of human CD4-bearing T lymphocytes. Infection with HTLV-2 has not been conclusively linked to lymphoproliferative disorders. We previously showed that human hematopoietic progenitor (CD34+) cells can be infected by HTLV-1 and that proviral sequences were maintained after differentiation of infected CD34+ cells in vitro and in vivo. To investigate the role of the Tax oncoprotein of HTLV on hematopoiesis, bicistronic lentiviral vectors were constructed encoding the HTLV-1 or HTLV-2 tax genes (Tax1 and Tax2, respectively) and the green fluorescent protein marker gene. Human hematopoietic progenitor (CD34+) cells were infected with lentivirus vectors, and transduced cells were cultured in a semisolid medium permissive for the development of erythroid, myeloid, and primitive progenitor colonies. Tax1-transduced CD34+ cells displayed a two- to fivefold reduction in the total number of hematopoietic clonogenic colonies that arose in vitro, in contrast to Tax2-transduced cells, which showed no perturbation of hematopoiesis. The ratio of colony types that developed from Tax1-transduced CD34+ cells remained unaffected, suggesting that Tax1 inhibited the maturation of relatively early, uncommitted hematopoietic stem cells. Since previous reports have linked Tax1 expression with initiation of apoptosis, lentiviral vector-mediated transduction of Tax1 or Tax2 was investigated in CEM and Jurkat T-cell lines. Ectopic expression of either Tax1 or Tax2 failed to induce apoptosis in T-cell lines. These data demonstrate that Tax1 expression perturbs development and maturation of pluripotent hematopoietic progenitor cells, an activity that is not displayed by Tax2, and that the suppression of hematopoiesis is not attributable to induction of apoptosis. Since hematopoietic progenitor cells may serve as a latently infected reservoir for HTLV infection in vivo, the different abilities of HTLV-1 and -2 Tax to suppress hematopoiesis may play a role in the respective clinical outcomes after infection with HTLV-1 or -2.

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 Abacavir, an anti–HIV-1 drug, targets TDP1-deficient adult T cell leukemia

2015 ◽  
Vol 1 (3) ◽  
pp. e1400203 ◽  
Author(s):  
Kohei Tada ◽  
Masayuki Kobayashi ◽  
Yoko Takiuchi ◽  
Fumie Iwai ◽  
Takashi Sakamoto ◽  
...  
Keyword(s):  
T Cell ◽  
Host Cells ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Chromosomal Dna ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Human T Cell ◽  
Hiv 1

Adult T cell leukemia (ATL) is an aggressive T cell malignancy caused by human T cell leukemia virus type 1 (HTLV-1) and has a poor prognosis. We analyzed the cytotoxic effects of various nucleoside analog reverse transcriptase inhibitors (NRTIs) for HIV-1 on ATL cells and found that abacavir potently and selectively kills ATL cells. Although NRTIs have minimal genotoxicities on host cells, the therapeutic concentration of abacavir induced numerous DNA double-strand breaks (DSBs) in the chromosomal DNA of ATL cells. DSBs persisted over time in ATL cells but not in other cell lines, suggesting impaired DNA repair. We found that the reduced expression of tyrosyl-DNA phosphodiesterase 1 (TDP1), a repair enzyme, is attributable to the cytotoxic effect of abacavir on ATL cells. We also showed that TDP1 removes abacavir from DNA ends in vitro. These results suggest a model in which ATL cells with reduced TDP1 expression are unable to excise abacavir incorporated into genomic DNA, leading to irreparable DSBs. On the basis of the above mechanism, we propose abacavir as a promising chemotherapeutic agent for ATL.

Sign in / Sign up

Export Citation Format

Share Document