Role of Interleukin-17 cytokine family in human T-cell lymphotropic virus type 1 (HTLV-1) infection and associated diseases.

BACKGROUND: Human T-lymphotropic virus (HTLV-1) is a neglected virus with worldwide distribution of over 10 million people and is the cause of two main associated diseases Adult T cell Leukemia-Lymphoma (ATLL), and HTLV-1-associated Myelopathy/Tropical Spastic paraparesis (HAM/TSP). The IL-17 cytokine family plays a crucial role in the host immunity against HTLV-1 and the development of associated disease. A systematic review was conducted to analyze all research reporting on the levels or expression of the IL-17 HTLV-1 infection and associated diseases. METHODS: The literature search was conducted in electronic databases including PubMed/Medline and Web of Sciences until January 31st, 2024, followed by the PRISMA guidelines. RESULTS: Our search revealed 20 eligible articles to be included in our study. The total number of cases studied was 1420, of which 386 were carriers without any symptoms, and were 176 ATLL and 237 HAM/TSP. The IL-17 cytokine family production or mRNA expression was higher in HAM/TSP patients but showed a trend toward reduction in the case of ATLL. CONCLUSIONS: Our results showed that while The IL-17 cytokine family plays a significant role in the immunopathogenesis of disease and clinical status of patients with inflammatory disorders such as HAM/TSP, IL-17 production is diminished and the RORC/IL-17 signaling pathway is downregulated during ATLL. Our data suggest that boosting the RORC/IL-17 signaling pathway in ATLL and using anti-IL-17 agents in HAM/TSP and other HTLV-related inflammatory conditions might benefit patients and improve their outcomes.

Adult T-cell leukemia/lymphoma with angioimmunoblastic T-cell lymphoma-like feature and molecularly confirmed RHOA Gly 17 Val (G17V) mutation: A case report.

We report a case of adult T-cell leukemia/lymphoma (ATLL) with angioimmunoblastic T-cell lymphoma (AITL/nTFHL-AI)-like feature. An 88-year-old Japanese woman with seropositive for the Human T-lymphotropic virus type 1 (HTLV-1) was incidentally diagnosed with generalized lymphadenopathy. Biopsy of the cervical lymph node demonstrated the proliferation of small- or medium-sized and large atypical lymphocytes associated with eosinophils, high endothelial venules, and clear cells. Immunohistochemical analysis revealed atypical lymphocytes were CD3- and CD4-positive. Atypical T cells bore the T-follicular helper phenotype (PD1, ICOS, and BCL6) and were positive for CD25 and chemokine receptor 4. Epstein-Barr virus encoded RNA-positive cells were scattered in the background via in situ hybridization. The histological findings were similar to those of AITL/nTFHL-AI; however, the immunohistochemical results did not exclude the possibility of ATLL. Southern blot analysis detected integration of HTLV-1 proviral DNA. The RHOA Gly 17 Val (G17V) mutation was detected by the peptide nucleic acid-locked nucleic acid clamp method. Finally, the patient was diagnosed with ATLL with AITL-like feature and exhibited a similar morphology, immunophenotype, and mutational signature to AITL/nTFHL-AI. ATLL mimics other types of T-cell lymphomas. Thus, in HTLV-1 endemic areas, routine screening for HTLV-1 serology is necessary to avoid misdiagnosis of other lymphoid malignancies.

Analysis of the Main Checkpoints of the JNK-MAPK Pathway in HTLV-1-Associated Leukemia/Lymphoma via Boolean Network Simulation.

The c-Jun N-terminal kinase (JNK) pathway is a signal transduction pathway that plays a critical role in cell growth and survival. Its dysregulation is related to various cancers, including adult T-cell leukemia/lymphoma (ATLL), an aggressive peripheral T-cell malignancy caused by human T-cell lymphotropic virus type 1 (HTLV-1) infection. There is currently no vaccine or definitive treatment for ATLL. This research aimed to identify the JNK-MAPK pathway checkpoints to identify possible therapeutic targets using Boolean network analysis. First, the genes involved in the JNK pathway and their interactions were identified and mapped. Next, a Boolean network analysis was performed using the R programming language, which suggested protein kinase B (AKT) and MAP kinase phosphatase (MKP) for further evaluation. Finally, to confirm the effect of these two genes, a clinical study was conducted among ATLL patients and healthy individuals. The quantitative real time polymerase chain reaction (qRT‒PCR) results revealed a statistically significant decrease in the expression of AKT and MKP in ATLL patients compared to normal controls. This highlights the potential role of these two genes as potential therapeutic targets in ATLL.

Clinical Features and Survival Outcome in Aggressive-Type Adult T-Cell Leukemia/Lymphoma Patients: Real-Life Experience of a Single Center from an HTLV-1 Endemic Country.

Background and Objectives: Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive T-cell lymphoproliferative disease associated with the human T-cell lymphotropic virus type I (HTLV-1). ATLL is a rare disease, found more frequently in HTLV-1-endemic areas, Romania being one of them. Despite treatment advances, the prognosis remains dismal. We aimed to describe the clinical, biological, and survival outcome features of Romanian patients with aggressive-type ATLL. Materials and Methods: We report the data of a prospective, observational, and unicentric study of all 20 patients diagnosed with lymphoma and acute types of ATLL at our center over the past 12 years. Data were collected from the patients' medical records. Results: Lymphoma-type ATLL (60%) was more common than acute-type ATLL (40%). Median age at diagnosis was 40.5 years, and most patients were female. Laboratory data revealed significant differences between acute and lymphoma-type ATLL, namely, higher leukocyte (p = 0.02) and lymphocyte counts (p = 0.02) and higher levels of corrected calcium (p = 0.001) in acute-type ATLL. All patients received chemotherapy, and only two underwent allogeneic stem cell transplantation. Only six patients obtained a complete or partial response to chemotherapy, mostly the lymphoma-type ones. The median survival for all patients was 6.37 months, with higher survival in the lymphoma-type ATLL (8.16 months) than in the acute-type (3.60 months). Normal calcium levels (p = 0.011), uric acid (p = 0.005), BUN score (p = 0.000), JCOG-PI moderate risk (p = 0.038), and obtaining complete or partial response (p = 0.037) were associated with higher survival. Conclusion: Aggressive-type ATLL among Romanian patients presents distinct characteristics, including younger age at diagnosis, female predominance, and higher incidence of lymphoma-type ATLL compared to currently reported data. Survival remains very low, with all subtypes experiencing a median survival of less than one year.

Pathogenicity and virulence of human T lymphotropic virus type-1 (HTLV-1) in oncogenesis: adult T-cell leukemia/lymphoma (ATLL).

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy of CD4+ T lymphocytes caused by human T lymphotropic virus type-1 (HTLV-1) infection. HTLV-1 was brought to the World Health Organization (WHO) and researchers to address its impact on global public health, oncogenicity, and deterioration of the host immune system toward autoimmunity. In a minority of the infected population (3-5%), it can induce inflammatory networks toward HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), or hijacking the infected CD4+ T lymphocytes into T regulatory subpopulation, stimulating anti-inflammatory signaling networks, and prompting ATLL development. This review critically discusses the complex signaling networks in ATLL pathogenesis during virus-host interactions for better interpretation of oncogenicity and introduces the main candidates in the pathogenesis of ATLL. At least two viral factors, HTLV-1 trans-activator protein (TAX) and HTLV-1 basic leucine zipper factor (HBZ), are implicated in ATLL manifestation, interacting with host responses and deregulating cell signaling in favor of infected cell survival and virus dissemination. Such molecules can be used as potential novel biomarkers for ATLL prognosis or targets for therapy. Moreover, the challenging aspects of HTLV-1 oncogenesis introduced in this review could open new venues for further studies on acute leukemia pathogenesis. These features can aid in the discovery of effective immunotherapies when reversing the gene expression profile toward appropriate immune responses gradually becomes attainable.

Live attenuated VZV vaccination induces antitumor immunity in ATLL patients.

Adult T cell leukemia/lymphoma (ATLL) is a CD4-positive peripheral T cell lymphoma caused by human T cell lymphotropic virus type 1 (HTLV-1). Although ATLL is quite difficult to be cured, up-regulation of cellular immunity such as HTLV-1 Tax-specific cytotoxic T lymphocytes (CTLs) has been proved to be important to obtain long-term survival. At present, no efficacious method to activate ATLL-specific cellular immunity is available. This study aimed to investigate whether live attenuated varicella-zoster virus (VZV) vaccination to ATLL can activate HTLV-1 Tax-specific cellular immune response. A total of 3 indolent- and 3 aggressive-type ATLL patients were enrolled. All aggressive-type patients had the VZV vaccination after completing anti-ATLL treatment including mogamulizumab, which is a monoclonal antibody for C-C chemokine receptor 4 antigen, plus combination chemotherapy, whereas all indolent-type patients had the VZV vaccination without any antitumor treatment. Cellular immune responses including Tax-specific CTLs were analyzed at several time points of pre- and post-VZV vaccination. After the VZV vaccination, a moderate increase in 1 of 3 indolent-type patients and obvious increase in all 3 aggressive-type patients in Tax-specific CTLs percentage were observed. The increase in the cell-mediated immunity against VZV was observed in all indolent- and aggressive-type patients after VZV vaccination. To conclude, VZV vaccination to aggressive-type ATLL patients after mogamulizumab plus chemotherapy led to the up-regulation of HTLV-1 Tax-specific CTLs without any adverse event. Suppression of regulatory T lymphocytes by mogamulizumab may have contributed to increase tumor immunity in aggressive-type ATLL patients. Japan Registry of Clinical Trials number, jRCTs051180107.

HTLV-1 persistent infection and ATLL oncogenesis.

Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus; whereas HTLV-1 mainly persists in the infected host cell as a provirus, it also causes a malignancy called adult T-cell leukemia/lymphoma (ATLL) in about 5% of infection. HTLV-1 replication is in most cases silent in vivo and viral de novo infection rarely occurs; HTLV-1 rather relies on clonal proliferation of infected T cells for viral propagation as it multiplies the number of the provirus copies. It is mechanistically elusive how leukemic clones emerge during the course of HTLV-1 infection in vivo and eventually cause the onset of ATLL. This review summarizes our current understanding of HTLV-1 persistence and oncogenesis, with the incorporation of recent cutting-edge discoveries obtained by high-throughput sequencing.

Momordica charantia phytoconstituents can inhibit human T-lymphotropic virus type-1 (HTLV-1) infectivity in vitro and in vivo.

There is an urgent need to find an effective therapy for life-threatening HTLV-1-associated diseases. Bitter melon (Momordica charantia) is considered a traditional herb with antiviral and anticancer properties and was tested in this study on HTLV-1 infectivity. GC-MS analyzed the alcoholic extract. In vitro assay was carried out using transfection of HUVEC cells by HTLV-1-MT2 cell line. The cells were exposed to alcoholic and aqueous extracts at 5,10, and 20 µg/mL concentrations. In vivo, mice were divided into four groups. Three groups were treated with HTLV-1-MT-2 cells as test groups and positive control, and PBS as the negative control group in the presence and absence of M. charantia extracts. Peripheral blood mononuclear cells (PBMCs), mesenteric lymph nodes (MLNs), and splenocytes were collected for HTLV-1-proviral load (PVL) assessment, TaqMan-qPCR. The GC-MS analysis revealed 36 components in M. charantia. The studies showed significant reductions in HTLV-1-PVL in the presence of extract in the HUVEC-treated groups (P = 0.001). Furthermore, the inhibitory effects of extracts on HTLV-1 infected mice showed significant differences in HTLV-1-PVL among M. charantia treated groups with untreated (P = 0.001). The T-cells in MLNs were significantly more susceptible to HTLV-1 than others (P = 0.001). There were significant differences among HTLV-1-infected cells in MLNs and splenocytes (P = 0.001 and 0.046, respectively). Also, aqueous and alcoholic extract-treated groups significantly affected HTLV-1-infected PBMCs (P = 0.002 and 0.009, respectively). M. charantia may have effective antiviral properties. The substantial compound of M. charantia could have inhibitory effects on the proliferation and transmission of HTLV-1 oncovirus.

Gene biomarkers and classifiers for various subtypes of HTLV-1-caused ATLL cancer identified by a combination of differential gene co­expression and support vector machine algorithms.

Adult T-cell leukemia/lymphoma (ATLL) is pathogen-caused cancer that is progressed after the infection by human T-cell leukemia virus type 1. Four significant subtypes comprising acute, lymphoma, chronic, and smoldering have been identified for this cancer. However, there are no trustworthy prognostic biomarkers for these subtypes. We utilized a combination of two powerful network-based and machine-learning algorithms including differential co-expressed genes (DiffCoEx) and support vector machine-recursive feature elimination with cross-validation (SVM-RFECV) methods to categorize disparate ATLL subtypes from asymptomatic carriers (ACs). The results disclosed the significant involvement of CBX6, CNKSR1, and MAX in chronic, MYH10 and P2RY1 in acute, C22orf46 and HNRNPA0 in smoldering subtypes. These genes also can classify each ATLL subtype from AC carriers. The integration of the results of two powerful algorithms led to the identification of reliable gene classifiers and biomarkers for diverse ATLL subtypes.

Gene expression study of host-human T-cell leukaemia virus type 1 (HTLV-1) interactions: adult T-cell leukaemia/lymphoma (ATLL).

BACKGROUND: In HTLV-1-associated malignant disease, adult T-cell leukaemia/lymphoma (ATLL), the interaction of virus and host was evaluated at the chemokines gene expression level. Also, IL-1ß and Caspase-1 expressions were evaluated to investigate the importance of pyroptosis in disease development and progression. METHODS AND RESULTS: The expression of host CCR6 and CXCR-3 and the HTLV-1 proviral load (PVL), Tax, and HBZ were assessed in 17 HTLV-1 asymptomatic carriers (ACs) and 12 ATLL patients using the reverse transcription-quantitative polymerase chain reaction (RT-qPCR), TaqMan method. Moreover, RT-qPCR, SYBR Green assay were performed to measure Caspase-1 and IL-1ß expression. HTLV-1-Tax did not express in 91.5% of the ATLLs, while HBZ was expressed in all ATLLs. The expression of CXCR3 dramatically decreased in ATLLs compared to ACs (p = 0.001). The expression of CCR6 was lower in ATLLs than ACs (p = 0.04). The mean of PVL in ATLL patients was statistically higher than ACs (p = 0.001). Furthermore, the expression of the IL-1ß between ATLLs and ACs was not statistically significant (p = 0.4). In contrast, there was a meaningful difference between Caspase-1 in ATLLs and ACs (p = 0.02). CONCLUSIONS: The present study indicated that in the first stage of ATLL malignancy toward acute lymphomatous, CXCR3 and its progression phase may target the pyroptosis process. Mainly, HBZ expression could be a novel therapeutic target.

Mortality and risk of progression to adult T cell leukemia/lymphoma in HTLV-1-associated myelopathy/tropical spastic paraparesis.

Human T cell leukemia virus 1 (HTLV-1) causes the functionally debilitating disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) as well as adult T cell leukemia lymphoma (ATLL). Although there were concerns that the mortality of HAM/TSP could be affected by the development of ATLL, prospective evidence was lacking in this area. In this 5-y prospective cohort study, we determined the mortality, prevalence, and incidence of ATLL in 527 HAM/TSP patients. The standard mortality ratio of HAM/TSP patients was 2.25, and ATLL was one of the major causes of death (5/33 deaths). ATLL prevalence and incidence in these patients were 3.0% and 3.81 per 1,000 person-y, respectively. To identify patients at a high risk of developing ATLL, flow cytometry, Southern blotting, and targeted sequencing data were analyzed in a separate cohort of 218 HAM/TSP patients. In 17% of the HAM/TSP patients, we identified an increase in T cells positive for cell adhesion molecule 1 (CADM1), a marker for ATLL and HTLV-1-infected cells. Genomic analysis revealed that somatic mutations of HTLV-1-infected cells were seen in 90% of these cases and 11% of them had dominant clone and developed ATLL in the longitudinal observation. In this study, we were able to demonstrate the increased mortality in patients with HAM/TSP and a significant effect of ATLL on their prognosis. Having dominant clonal expansion of HTLV-1-infected cells with ATLL-associated somatic mutations may be important characteristics of patients with HAM/TSP who are at an increased risk of developing ATLL.

Small RNA Profiling in an HTLV-1-Infected Patient with Acute Adult T-Cell Leukemia-Lymphoma at Diagnosis and after Maintenance Therapy: A Case Study.

Small RNAs (sRNAs) are epigenetic regulators of essential biological processes associated with the development and progression of leukemias, including adult T-cell leukemia/lymphoma (ATLL) caused by human T-cell lymphotropic virus type 1 (HTLV-1), an oncogenic human retrovirus originally discovered in a patient with adult T-cell leukemia/lymphoma. Here, we describe the sRNA profile of a 30-year-old woman with ATLL at the time of diagnosis and after maintenance therapy with the aim of correlating expression levels with response to therapy.

Oral histone deacetylase inhibitor tucidinostat (HBI-8000) in patients with relapsed or refractory adult T-cell leukemia/lymphoma: Phase IIb results.

This multicenter, prospective phase IIb trial evaluating the efficacy and safety of tucidinostat (HBI-8000) in patients with relapsed or refractory (R/R) adult T-cell leukemia/lymphoma (ATLL) was undertaken in Japan. Eligible patients had R/R ATLL and had failed standard of care treatment with chemotherapy and with mogamulizumab. Twenty-three patients received tucidinostat 40 mg orally twice per week and were included in efficacy and safety analyses. The primary end-point was objective response rate (ORR) assessed by an independent committee. The ORR was 30.4% (95% confidence interval [CI], 13.2, 52.9]. Median progression-free survival was 1.7 months (95% CI, 0.8, 7.4), median duration of response was 9.2 months (95% CI, 2.6, not reached), and median overall survival was 7.9 months (95% CI, 2.3, 18.0). All patients experienced adverse events (AEs), which were predominantly hematologic and gastrointestinal. Incidence of grade 3 or higher AEs was 78.3%; most were laboratory abnormalities (decreases in platelets, neutrophils, white blood cells, and hemoglobin). Tucidinostat was well tolerated with AEs that could be mostly managed with supportive care and dose modifications. Tucidinostat is a meaningful treatment option for R/R ATLL patients; further investigation is warranted.

HTLV, a multi organ oncovirus.

Human T lymphotropic virus (HTLV-I) is a retrovirus that has been recognized as a causative agent of two crucidal diseases, HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) and Adult T cell Leukemia-Lymphoma (ATLL). The virus not only induces those diseases in a small proportion of HTLV-I carriers (3-5%) but also it is associated with other diseases such as HTLV-I-Associated Arthropathy (HAAP), Cutaneous T Cell Lymphoma (CTCL), Graves' disease, uveitis, polymyositis, chronic respiratory diseases, lymphadenitis and dermatitis. Furthermore, HTLV related and accelerated disorders were more investigated, and the factors that might implicate in the development or progression of diseases have been discussed. We founded 13 categories of non-associated disease in studies such as Reproductive Disorders, Coronary Artery Disease (CAD), non -ATLL lymphoma, Co-infection, non-HAM/TSP neurological associated disease, non ATLL cutaneous associated disease, Autoimmune-Inflammatory related disease, Kidney disease, Liver disease, Respiratory disease, TB disease and Thyroid disease. With regard to the reviewed studies suggested HTLV-I disorders can divide into three manifests; related, accelerated and associated disease. However, interaction between HTLV-I infection and host immune response was complicated and vague. Some infectious patients indicated the involvement of inflammatory response of immune system, but in other individuals function of anti-inflammatory elements was observed. For a better understanding of this classification, more systematic studies should be designed and need to provide a global network to control and prevent HTLV affiliated diseases.

Exploration of mRNAs and miRNA classifiers for various ATLL cancer subtypes using machine learning.

BACKGROUND: Adult T-cell Leukemia/Lymphoma (ATLL) is a cancer disease that is developed due to the infection by human T-cell leukemia virus type 1. It can be classified into four main subtypes including, acute, chronic, smoldering, and lymphoma. Despite the clinical manifestations, there are no reliable diagnostic biomarkers for the classification of these subtypes. METHODS: Herein, we employed a machine learning approach, namely, Support Vector Machine-Recursive Feature Elimination with Cross-Validation (SVM-RFECV) to classify the different ATLL subtypes from Asymptomatic Carriers (ACs). The expression values of multiple mRNAs and miRNAs were used as the features. Afterward, the reliable miRNA-mRNA interactions for each subtype were identified through exploring the experimentally validated-target genes of miRNAs. RESULTS: The results revealed that miR-21 and its interactions with DAAM1 and E2F2 in acute, SMAD7 in chronic, MYEF2 and PARP1 in smoldering subtypes could significantly classify the diverse subtypes. CONCLUSIONS: Considering the high accuracy of the constructed model, the identified mRNAs and miRNA are proposed as the potential therapeutic targets and the prognostic biomarkers for various ATLL subtypes.

Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases.

BACKGROUND: Human T cell Leukemia virus type 1 (HTLV-I) is etiologically linked to adult T cell leukemia/lymphoma (ATL) and an inflammatory neurodegenerative disease called HTLV-I-associated myelopathy or tropical spastic paraparesis (HAM/TSP). The exact genetic or epigenetic events and/or environmental factors that influence the development of ATL, or HAM/TSP diseases are largely unknown. The tumor suppressor gene, Fragile Histidine Triad Diadenosine Triphosphatase (FHIT), is frequently lost in cancer through epigenetic modifications and/or deletion. FHIT is a tumor suppressor acting as genome caretaker by regulating cellular DNA repair. Indeed, FHIT loss leads to replicative stress and accumulation of double DNA strand breaks. Therefore, loss of FHIT expression plays a key role in cellular transformation. METHODS: Here, we studied over 400 samples from HTLV-I-infected individuals with ATL, TSP/HAM, or asymptomatic carriers (AC) for FHIT loss and expression. We examined the epigenetic status of FHIT through methylation specific PCR and bisulfite sequencing; and correlated these results to FHIT expression in patient samples. RESULTS: We found that epigenetic alteration of FHIT is specifically found in chronic and acute ATL but is absent in asymptomatic HTLV-I carriers and TSP/HAM patients' samples. Furthermore, the extent of FHIT methylation in ATL patients was quantitatively comparable in virus-infected and virus non-infected cells. We also found that longitudinal HTLV-I carriers that progressed to smoldering ATL and descendants of ATL patients harbor FHIT methylation. CONCLUSIONS: These results suggest that germinal epigenetic mutation of FHIT represents a preexisting mark predisposing to the development of ATL diseases. These findings have important clinical implications as patients with acute ATL are rarely cured. Our study suggests an alternative strategy to the current "wait and see approach" in that early screening of HTLV-I-infected individuals for germinal epimutation of FHIT and early treatment may offer significant clinical benefits.

Pathophysiological significance of N-myc downstream-regulated gene 2 in cancer development through protein phosphatase 2A phosphorylation regulation.

N-myc downstream-regulated gene 2 (NDRG2) is a candidate tumor suppressor in various cancers, including adult T-cell leukemia/lymphoma (ATLL). NDRG2, as a stress-responsive protein, is induced by several stress-related signaling pathways and NDRG2 negatively regulates various signal transduction pathways. Although it has not been found to function alone, NDRG2 binds serine/threonine protein phosphatase 2A (PP2A), generating a complex that is involved in the regulation of various target proteins. The main function of NDRG2 is to maintain cell homeostasis by suppressing stress-induced signal transduction; however, in cancer, genomic deletions and/or promoter methylation may inhibit the expression of NDRG2, resulting in enhanced tumor development through overactivated signal transduction pathways. A wide variety of tumors develop in Ndrg2-deficient mice, including T-cell lymphoma, liver, lung and other tumors, the characteristics of which are similar to those in Pten-deficient mice. In particular, PTEN is a target molecule of the NDRG2/PP2A complex, which enhances PTEN phosphatase activity by dephosphorylating residues in the PTEN C-terminal region. In ATLL cells, loss of NDRG2 expression leads to the failed recruitment of PP2A to PTEN, resulting in the inactivation of PTEN phosphatase with phosphorylation, ultimately leading to the activation of PI3K/AKT. Thus, NDRG2, as a PP2A adaptor, regulates the global phosphorylation of important signaling molecules. Moreover, the downregulation of NDRG2 expression by long-term stress-induced methylation is directly correlated with the development of ATLL and other cancers. Thus, NDRG2 might be important for the development of stress-induced leukemia and other cancers and has become an important target for novel molecular therapies.

Identification of joint gene players implicated in the pathogenesis of HTLV-1 and BLV through a comprehensive system biology analysis.

BACKGROUND: Human T-cell lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV) are oncogenic viruses that induce adult T cell leukemia/lymphoma (ATLL) and enzootic bovine leukosis (EBL), respectively. HTLV-1 principally infects CD4+ T cells comprising regulatory T cells (Tregs), T helper 1 (Th1), and T helper 2 (Th2), while BLV infects B lymphocytes. Both viruses may impel cell proliferation and malignancy. METHODS: To survey the transcriptomic variations due to HTLV-1 and BLV infection and further hematologic malignancies, differential expression genes (DEGs) were explored between leukemia and normal samples using the DESeq2 package. Gene set enrichment analyses (GSEA) were then performed to identify significant gene sets using the FGSEA package. Afterward, the protein-protein interaction (PPI) networks were reconstructed using the STRING online database. Eventually, the hub significant genes and modules were determined through network analysis and MCODE algorithm, respectively. RESULTS: Our results uncloaked that four common functional gene sets including mitotic-spindle, G2M-checkpoint, E2F-targets, and MYC-targets-V1 are involved in the human and ovine hosts. Furthermore, twelve up-regulated hub genes including BIRC5, CCNA2, CCNB2, BUB1, DLGAP5, TOP2A, PBK, ASPM, UBE2C, CEP55, KIF20A, and NUSAP1 were identified which were similarly activated in both human and ovine hosts. They mostly participate in pathways including cell cycle, cell division, DNA damage responses, growth factors production, and p53 signaling pathway. The dysregulated hub genes and pathways seem to be involved in the development and progression of the infected cells toward malignancy. CONCLUSION: There is common gene groups between HTLV-1 and BLV infections that promote viral malignancy through enhancing cell proliferation and overall survival of cancer cells. The dysregulated genes and pathways may be the efficient candidates for the therapy of the mentioned life-threatening diseases.

Decoding pathogenesis factors involved in the progression of ATLL or HAM/TSP after infection by HTLV-1 through a systems virology study.

BACKGROUND: Human T-cell Leukemia Virus type-1 (HTLV-1) is a retrovirus that causes two diseases including Adult T-cell Leukemia/Lymphoma (ATLL cancer) and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP, a neurodegenerative disease) after a long latency period as an asymptomatic carrier (AC). There are no obvious explanations about how each of the mentioned diseases develops in the AC carriers. Finding the discriminative molecular factors and pathways may clarify the destiny of the infection. METHODS: To shed light on the involved molecular players and activated pathways in each state, differentially co-expressed modules (DiffCoEx) algorithm was employed to identify the highly correlated genes which were co-expressed differently between normal and ACs, ACs and ATLL, as well as ACs and HAM/TSP samples. Through differential pathway analysis, the dysregulated pathways and the specific disease-genes-pathways were figured out. Moreover, the common genes between the member of DiffCoEx and differentially expressed genes were found and the specific genes in ATLL and HAM/TSP were introduced as possible biomarkers. RESULTS: The dysregulated genes in the ATLL were mostly enriched in immune and cancer-related pathways while the ones in the HAM/TSP were enriched in immune, inflammation, and neurological pathways. The differential pathway analysis clarified the differences between the gene players in the common activated pathways. Eventually, the final analysis revealed the involvement of specific dysregulated genes including KIRREL2, RAB36, and KANK1 in HAM/TSP as well as LTB4R2, HCN4, FZD9, GRIK5, CREB3L4, TACR2, FRMD1, LHB, FGF3, TEAD3, GRIN2D, GNRH2, PRLH, GPR156, and CRHR2 in ATLL. CONCLUSION: The identified potential prognostic biomarkers and therapeutic targets are proposed as the most important platers in developing ATLL or HAM/TSP. Moreover, the proposed signaling network clarifies the differences between the functional players in the activated pathways in ACs, ATLL, and HAM/TSP.

Mechanisms Involved in the Promoting Activity of Fibroblasts in HTLV-1-Mediated Lymphomagenesis: Insights into the Plasticity of Lymphomatous Cells.

Among the mechanisms leading to progression to Adult T-cell Leukaemia/Lymphoma in Human T-cell Leukaemia Virus type 1 (HTLV-1)-infected subjects, the contribution of stromal components remains poorly understood. To dissect the role of fibroblasts in HTLV-1-mediated lymphomagenesis, transcriptome studies, cytofluorimetric and qRT-PCR analyses of surface and intracellular markers linked to plasticity and stemness in coculture, and in vivo experiments were performed. A transcriptomic comparison between a more lymphomagenic (C91/III) and the parental (C91/PL) cell line evidenced hyperactivation of the PI3K/Akt pathway, confirmed by phospho-ELISA and 2-DE and WB analyses. C91/III cells also showed higher expression of mesenchymal and stemness genes. Short-term coculture with human foreskin fibroblasts (HFF) induced these features in C91/PL cells, and significantly increased not only the cancer stem cells (CSCs)-supporting CD10+GPR77+ HFF subpopulation, but also the percentage of ALDH1bright C91/PL cells. A non-cytotoxic acetylsalicylic acid treatment decreased HFF-induced ALDH1bright C91/PL cells, downregulated mesenchymal and stemness genes in cocultured cells, and delayed lymphoma growth in immunosuppressed mice, thus hindering the supportive activity of HFF on CSCs. These data suggest that crosstalk with HFF significantly intensifies the aggressiveness and plasticity of C91/PL cells, leading to the enrichment in lymphoma-initiating cells. Additional research is needed to better characterize these preliminary findings.