scholarly journals Immune Senescence-Related Gene Expression Profile in CD4+ T-Lymphocytes of HTLV-1 Asymptomatic Carriers and Patients with Adult T-Cell Leukemia/Lymphoma (ATLL): A Brazilian Preliminary Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4323-4323
Author(s):  
José Roberto Assis Filho ◽  
Hebert Fabricio Culler ◽  
Debora Levy ◽  
Karolliny Silva de Oliveira ◽  
Daniel Silva Nogueira ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
Pilot Study ◽  
T Lymphocytes ◽  
Real Time ◽  
Control Group ◽  
Cell Leukemia ◽  
Cd4 Cells ◽  
Asymptomatic Carriers ◽  
Adult T Cell Leukemia

Abstract Introduction: Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive neoplasm caused by the human T-lymphotropic virus type 1 (HTLV-1). It is estimated, worldwide, that at least 5-10 million people carry HTLV-1 and 2-5% out of them will develop ATLL. Previously, our group demonstrated an increase of cells in G0/G1 phase of cell cycle and aneuploidy in CD4+ T-cells in HTLV-1 asymptomatic carriers [1]. These findings may reflect an adverse intracellular environment, caused by genetic stress due to viral particles inserted into host DNA. Intracellular mechanisms aiming to control and prevent replication of cells carrying genetic aberrations in genes involved in cell cycle regulation, DNA repair and apoptosis could be activated to hold cell division while DNA damage is repaired. Based on this hypothesis, delay of cell cycle in G0/G1 may be a step in the process of oncogenesis [1]. Herein, we did a pilot study in order to analyze the pattern of expression of a set of genes involved in cell cycle control and senescence in CD4+ T-lymphocytes of HTLV-1 infected individuals searching for additional genetic abnormalities in this setting. Methods: Peripheral blood samples were tested obtained from five HTLV-1 asymptomatic carriers and four ATLL patients for this pilot study. T-CD4+ cells were isolated in magnetic column followed by RNA extraction. Subsequently, it was converted into cDNA for the assays of the real-time quantitative polymerase chain reaction (qRT-PCR) in microplates of 96 wells previously customized with 44 senescence related genes pursued from ThermoFischer Scientific. A pool of five samples from healthy individuals (control group) was used as a calibrator. RNA transcription was measured using 7500 Fast real time PCR system (Applied Biosystems) and data were collected by the 7500 software v2.0.5 (Applied Biosystems). The expression levels of the target genes were calculated using the Livak and Schmittgen (2001) method [2]. The mRNA expression was normalized using the β-glucuronidase (GUSB) gene (Applied Biosystems, cod. Hs99999908_m1) and those genes with expression ≥ 2x or ≤ 2x in comparison to control group were considered as differentially expressed and were chosen to be validated in a secondary cohort of thirty HTLV-1 infected individuals. Results: In HTLV-1 asymptomatic carriers the median age was 55 years (37-62 years) and 20% (1/5) of them were males, in ATLL patients: 45 years (38-66 years) and 100% (4/4) were females, while the control group had median age of 43 years (22-62 years) and 60% (3/5) were males. Among the ATLL group, 50% (2/4) were classified as smoldering, 25% (1/4) were acute and 25% (1/4) were lymphomatous, according to Shimoyama classification [3]. COL3A1, SPARC and TWIST1 genes were overexpressed and CDKN1A, ID1, IFNG and TERT were suppressed in HTLV-1 asymptomatic carriers when compared to healthy controls. HTLV-1 infected and ATLL patients showed TWIST1 and COL3A1 genes overexpressed and IFNG, CDKN1A and TERT repressed (Figure 1 and 2). The ALDH1, FN1, NOX4 and COL1A1 genes did not amplified. Conclusion: These preliminaries results showed for the first time that HTLV-1 asymptomatic carriers present a set of genes differentially expressed in T-CD4+ cells, especially SPARC, TWIST1, COL3A1, CDNK1A and IFNG. These results will be confirmed in a validation cohort. We expected that this data shed some light on the comprehension of the cell microenvironment of the T-CD4+ lymphocyte in HTLV-1 asymptomatic carriers. Furthermore, we will be able to understand potential mechanisms associated with leukemogenesis in chronic infection by this virus, explaining eventual progression to ATLL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Downregulation of CDKN1A in Adult T-Cell Leukemia/Lymphoma despite Overexpression of CDKN1A in Human T-Lymphotropic Virus 1-Infected Cell Lines

2010 ◽  
Vol 84 (14) ◽  
pp. 6966-6977 ◽  
Author(s):  
Masaaki Watanabe ◽  
Shingo Nakahata ◽  
Makoto Hamasaki ◽  
Yusuke Saito ◽  
Yohei Kawano ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
T Lymphocytes ◽  
Infected Cell ◽  
Cell Lines ◽  
Cytoplasmic Localization ◽  
Cell Leukemia ◽  
T Lymphotropic Virus ◽  
Adult T Cell Leukemia ◽  
Atll Cell

ABSTRACT Human T-lymphotropic virus 1 (HTLV-1) causes an aggressive malignancy of T lymphocytes called adult T-cell leukemia/lymphoma (ATLL), and expression of HTLV-1 Tax influences cell survival, proliferation, and genomic stability in the infected T lymphocytes. Cyclin-dependent kinase inhibitor 1A (CDKN1A/p21waf1/Cip1) is upregulated by Tax, without perturbation of cell cycle control. During an analysis of the gene expression profiles of ATLL cells, we found very low expression of CDKN1A in ATLL-derived cell lines and ATLL cells from patient samples, and epigenetic abnormalities including promoter methylation are one of the mechanisms for the low CDKN1A expression in ATLL cells. Three HTLV-1-infected cell lines showed high levels of expression of both CDKN1A and Tax, but expression of CDKN1A was detected in only two of six ATLL-derived cell lines. In both the HTLV-1-infected and ATLL cell lines, we found that activated Akt phosphorylates CDKN1A at threonine 145 (T145), leading to cytoplasmic localization of CDKNIA. In HTLV-1-infected cell lines, cytoplasmic CDKN1A did not inhibit the cell cycle after UV irradiation; however, following treatment with LY294002, a PI3K inhibitor, CDKN1A was dephosphorylated and relocalized to the nucleus, resulting in suppression of the cell cycle. In the ATLL cell lines, treatment with LY294002 did not inhibit the cell cycle but induced apoptosis with the cytoplasmic localization. Therefore, the low CDKN1A expression in ATLL cells may be a key player in ATLL leukemogenesis, and the abnormal genomic methylation may influence the expression of not only HTLV-1 Tax but also CDKN1A during long-term development of ATLL from the HTLV-1-infected T lymphocytes.

scholarly journals Identification of Two New HLA-A*1101-Restricted Tax Epitopes Recognized by Cytotoxic T Lymphocytes in an Adult T-Cell Leukemia Patient after Hematopoietic Stem Cell Transplantation

2005 ◽  
Vol 79 (15) ◽  
pp. 10088-10092 ◽  
Author(s):  
Nanae Harashima ◽  
Ryuji Tanosaki ◽  
Yukiko Shimizu ◽  
Kiyoshi Kurihara ◽  
Takao Masuda ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
T Lymphocytes ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cytotoxic T Lymphocytes ◽  
Cell Leukemia ◽  
Hematopoietic Stem ◽  
Adult T Cell Leukemia

ABSTRACT We previously reported that Tax-specific CD8+ cytotoxic T lymphocytes (CTLs), directed to single epitopes restricted by HLA-A2 or A24, expanded in vitro and in vivo in peripheral blood mononuclear cells (PBMC) from some adult T-cell leukemia (ATL) patients after but not before allogeneic hematopoietic stem cell transplantation (HSCT). Here, we demonstrated similar Tax-specific CTL expansion in PBMC from another post-HSCT ATL patient without HLA-A2 or A24, whose CTLs equally recognized two newly identified epitopes, Tax88-96 and Tax272-280, restricted by HLA-A11, suggesting that these immunodominant Tax epitopes are present in the ATL patient in vivo.

scholarly journals Tumor Suppressor Inactivation in the Pathogenesis of Adult T-Cell Leukemia

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Christophe Nicot
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
Tumor Suppressor ◽  
Cell Cycle Arrest ◽  
Tumor Suppressors ◽  
Epigenetic Mechanisms ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Cycle Arrest

Tumor suppressor functions are essential to control cellular proliferation, to activate the apoptosis or senescence pathway to eliminate unwanted cells, to link DNA damage signals to cell cycle arrest checkpoints, to activate appropriate DNA repair pathways, and to prevent the loss of adhesion to inhibit initiation of metastases. Therefore, tumor suppressor genes are indispensable to maintaining genetic and genomic integrity. Consequently, inactivation of tumor suppressors by somatic mutations or epigenetic mechanisms is frequently associated with tumor initiation and development. In contrast, reactivation of tumor suppressor functions can effectively reverse the transformed phenotype and lead to cell cycle arrest or death of cancerous cells and be used as a therapeutic strategy. Adult T-cell leukemia/lymphoma (ATLL) is an aggressive lymphoproliferative disease associated with infection of CD4 T cells by the Human T-cell Leukemia Virus Type 1 (HTLV-I). HTLV-I-associated T-cell transformation is the result of a multistep oncogenic process in which the virus initially induces chronic T-cell proliferation and alters cellular pathways resulting in the accumulation of genetic defects and the deregulated growth of virally infected cells. This review will focus on the current knowledge of the genetic and epigenetic mechanisms regulating the inactivation of tumor suppressors in the pathogenesis of HTLV-I.

scholarly journals Chromosome aberrations in T lymphocytes carrying adult T-cell leukemia- associated antigens (ATLA) from healthy adults

Blood ◽  
1983 ◽  
Vol 61 (1) ◽  
pp. 205-207 ◽  
Author(s):  
S Fukuhara ◽  
Y Hinuma ◽  
YI Gotoh ◽  
H Uchino
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Chromosome Aberrations ◽  
Unknown Origin ◽  
Healthy Adults ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
The Third ◽  
Abnormal Cells

Abstract Chromosomes were studied in cultured T lymphocytes carrying adult T- cell leukemia-associated antigens (ATLA) that were obtained from five Japanese anti-ATLA seropositive healthy adults. Chromosomally abnormal cells were observed in three of the five healthy adults, and these cells were clonal in two subjects. All cells examined in one subject had rearrangements of chromosome nos. 7 and 14. Clonal cells from the second had a minute chromosome of unknown origin. A few cells in the third had nonclonal rearrangements of chromosomes. Thus, ATLA-positive T lymphocytes in some anti-ATLA seropositive healthy people have chromosome aberrations.

Expression of PD-1 and PD-L1 on cytotoxic T lymphocytes and immune deficiency in a patient with adult T cell leukemia/lymphoma

2017 ◽  
Vol 97 (2) ◽  
pp. 359-360 ◽  
Author(s):  
Toyoshi Yanagihara ◽  
Yuki Ikematsu ◽  
Koji Kato ◽  
Akiko Yonekawa ◽  
Satoko Ideishi ◽  
...  
Keyword(s):  
Immune Deficiency ◽  
T Cell ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia

scholarly journals Effective treatment of a murine model of adult T-cell leukemia using depsipeptide and its combination with unmodified daclizumab directed toward CD25

Blood ◽  
2009 ◽  
Vol 113 (6) ◽  
pp. 1287-1293 ◽  
Author(s):  
Jing Chen ◽  
Meili Zhang ◽  
Wei Ju ◽  
Thomas A. Waldmann
Keyword(s):  
T Cell ◽  
Murine Model ◽  
Therapeutic Efficacy ◽  
Severe Combined Immunodeficiency ◽  
Control Group ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Antitumor Effects ◽  
Adult T Cell Leukemia ◽  
Human T Cell

Abstract Adult T-cell leukemia (ATL) is caused by human T-cell lymphotropic virus I (HTLV-1) and is an aggressive malignancy of CD4, CD25-expressing leukemia, and lymphoma cells. There is no accepted curative therapy for ATL. Depsipeptide, a histone deacetylase inhibitor, has demonstrated major antitumor effects in leukemias and lymphomas. In this study, we investigated the therapeutic efficacy of depsipeptide alone and in combination with daclizumab (humanized anti-Tac) in a murine model of human ATL. The Met-1 ATL model was established by intraperitoneal injection of ex vivo leukemic cells into nonobese diabetic/severe combined immunodeficiency mice. Either depsipeptide, given at 0.5 mg/kg every other day for 2 weeks, or daclizumab, given at 100 μg weekly for 4 weeks, inhibited tumor growth as monitored by serum levels of soluble IL-2R-α (sIL-2R-α) and soluble β2-microglobulin (β2μ) (P < .001), and prolonged survival of the leukemia-bearing mice (P < .001) compared with the control group. Combination of depsipeptide with daclizumab enhanced the antitumor effect, as shown by both sIL-2R-α and β2μ levels and survival of the leukemia-bearing mice, compared with those in the depsipeptide or daclizumab alone groups (P < .001). The significantly improved therapeutic efficacy by combining depsipeptide with daclizumab supports a clinical trial of this combination in the treatment of ATL.

scholarly journals Elevation of Memory Cytotoxic T Lymphocytes, Including Human T Lymphotropic Virus Type 1 Tax-Specific and Hepatitis Virus Type C-Specific Cytotoxic T Lymphocytes, in a Patient with Adult T-Cell Leukemia/Lymphoma and Hepatocellular Carcinoma

2020 ◽  
Vol 13 (2) ◽  
pp. 802-806
Author(s):  
Tatsuro Jo ◽  
Yohei Kaneko ◽  
Takayuki Oishi ◽  
Kaori Matsuzaka ◽  
Haruna Shioya ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Virus Type ◽  
Hepatitis Virus ◽  
Cell Leukemia ◽  
T Lymphotropic Virus ◽  
Adult T Cell Leukemia ◽  
Type C

Herein, we present the case of a patient who suffered from adult T-cell leukemia/lymphoma (ATLL) and hepatocellular carcinoma (HCC) after obtaining a sustained virological response following treatment with a direct-acting antiviral (DAA) at different points in time. The patient went into complete remission (CR) for ATLL. Unfortunately, subsequent relapse of ATLL was observed. This situation was overcome using chemotherapy with pegylated interferon alpha-2b. Human T lymphotropic virus type 1 Tax-specific cytotoxic T lymphocytes (CTLs) were recognized after obtaining second CR, and those CTLs have been maintained for many years. After 4 years from the second CR, chronic hepatitis type C was treated with a DAA, and sustained virological response was attained. However, the occurrence of HCC was detected. Surprisingly, the tumor disappeared spontaneously. Hepatitis virus type C-specific CTLs were also detected in the patient. T-cell receptor (TCR) V beta gene repertoire analyses revealed oligoclonal expansion of effector and memory CTLs. The number of CTLs expressing the TCR V beta 13.1 has increased over the years since HCC occurrence. The activation and maintenance of anticancer cellular immunity may have allowed the patient to obtain long-term survival and overcome two lethal neoplasms.

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