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.

Human T-cell lymphotropic virus type 1 (HTLV-1) grip on T-cells: investigating the viral tapestry of activation.

INTRODUCTION: Human T-cell Lymphotropic virus type 1 (HTLV-1) belongs to retroviridae which is connected to two major diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and Adult T-cell leukemia/lymphoma (ATLL). This study aims to investigate the mRNA expressions of key proteins correlated to T-cell activation in asymptomatic carriers (ACs) HTLV-1 infected patients, shedding light on early molecular events and T-cell activation following HTLV-1 infection. MATERIAL AND METHODS: The study involved 40 participants, including 20 ACs and 20 healthy subjects. Blood samples were collected, ELISA assessment for screening and confirmation with PCR for Trans-activating transcriptional regulatory protein (Tax) and HTLV-1 basic leucine zipper factor (HBZ) of the HTLV-1 were done. mRNA expressions of C-terminal Src kinase (CSK), Glycogen Synthase Kinase-3 Beta (GSK3ß), Mitogen-Activated Protein Kinase 14 (MAP3K14 or NIK), Phospholipase C Gamma-1 (PLCG1), Protein Tyrosine Phosphatase non-Receptor Type 6 (PTPN6) and Mitogen-Activated Protein Kinase Kinase Kinase-7 (SLP-76) and Mitogen-Activated Protein Kinase14 (MAP3K7 or TAK1) were assayed using RT-qPCR. Statistical analyses were performed using PRISM and SPSS software. RESULTS: While there were no significant upregulation in CSK and PTPN6 in ACs compared to healthy individuals, expression levels of GSK3ß, MAP3K14, PLCG1, SLP-76, and TAK1 were significantly higher in ACs compared to healthy subjects which directly contributes to T-cell activation in the HTLV-1 ACs. CONCLUSION: HTLV-1 infection induces differential mRNA expressions in key proteins associated with T-cell activation. mRNAs related to T-cell activation showed significant upregulation compared to PTPN6 and CSK which contributed to T-cell regulation. Understanding these early molecular events in ACs may provide potential markers for disease progression and identify therapeutic targets for controlling viral replication and mitigating associated diseases. The study contributes novel insights to the limited literature on T-cell activation and HTLV-1 pathogenesis.

Complete Rescue of HTLV-1p12KO Infectivity by Depletion of Monocytes Together with NK and CD8+ T Cells.

The transient depletion of monocytes alone prior to exposure of macaques to HTLV-1 enhances both HTLV-1WT (wild type) and HTLV-1p12KO (Orf-1 knockout) infectivity, but seroconversion to either virus is not sustained over time, suggesting a progressive decrease in virus expression. These results raise the hypotheses that either HTLV-1 persistence depends on a monocyte reservoir or monocyte depletion provides a transient immune evasion benefit. To test these hypotheses, we simultaneously depleted NK cells, CD8+ T cells, and monocytes (triple depletion) prior to exposure to HTLV-1WT or HTLV-1p12KO. Remarkably, triple depletion resulted in exacerbation of infection by both viruses and complete rescue of HTLV-1p12KO infectivity. Following triple depletion, we observed rapid and sustained seroconversion, high titers of antibodies against HTLV-1 p24Gag, and frequent detection of viral DNA in the blood and tissues of all animals when compared with depletion of only CD8+ and NK cells, or monocytes alone. The infection of macaques with HTLV-1WT or HTLV-1p12KO was associated with higher plasma levels of IL-10 after 21 weeks, while IL-6, IFN-γ, IL-18, and IL-1ß were only elevated in animals infected with HTLV-1WT. The repeat depletion of monocytes, NK, and CD8+ cells seven months following the first exposure to HTLV-1 did not further exacerbate viral replication. These results underscore the contribution of monocytes in orchestrating anti-viral immunity. Indeed, the absence of orf-1 expression was fully compensated by the simultaneous depletion of CD8+ T cells, NK cells, and monocytes, underlining the primary role of orf-1 in hijacking host immunity.

Stem cell therapy for HTLV-1 induced adult T-cell leukemia/lymphoma (ATLL): A comprehensive review.

Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive form of cancer associated with human T-cell lymphotropic virus type 1 (HTLV-1) infection. The emerging field of stem cell therapies for ATLL is discussed, highlighting the potential of hematopoietic stem cell transplantation (HSCT) and genetically modified stem cells. HSCT aims to eradicate malignant T-cells and restore a functional immune system through the infusion of healthy donor stem cells. Genetically modified stem cells show promise in enhancing their ability to target and eliminate ATLL cells. The article presents insights from preclinical studies and limited clinical trials, emphasizing the need for further research to establish the safety, efficacy, and long-term outcomes of stem cell therapies for ATLL and challenges associated with these innovative approaches are also explored. Overall, stem cell therapies hold significant potential in revolutionizing ATLL treatment, and ongoing clinical trials aim to determine their benefits in larger patient populations.

Upregulation of Enhancer of Zeste Homolog 2 (EZH2) with Associated pERK Co-Expression and PRC2 Complex Protein SUZ12 Correlation in Adult T-Cell Leukemia/Lymphoma.

EZH2, a subunit of the polycomb repressive complex 2 (PRC2), is an important methyltransferase that catalyzes the trimethylation of histone H3 at lysine 27 (H3K27me3). EZH2 is overexpressed in various malignancies. Here, we investigated EZH2 expression and potential signaling molecules that correlate with EZH2 expression in ATLL and other T-cell neoplasms. Immunohistochemical staining (IHC) was performed for EZH2, pERK, MYC, and pSTAT3 on 43 ATLL cases and 104 cases of other T-cell neoplasms. Further IHC studies were conducted for Ki-67, SUZ12, and H3K27me3 on ATLL cases. All ATLL cases showed EZH2 overexpression. In other T-cell neoplasms, a high prevalence of EZH2 overexpression was identified (86%), except for T-PLL (33%). In ATLL, EZH2 overexpression correlated with pERK co-expression (86%), while only a small subset of cases showed MYC (7%) or pSTAT3 (14%) co-expression. In the other T-cell neoplasms, there was a variable, but higher, co-expression of EZH2 with pERK, MYC, and pSTAT3. In ATLL, enhanced EZH2 expression correlated with higher Ki-67 staining, SUZ12 (another PRC2 subunit), and H3K27me3 co-expression. In conclusion, EZH2 is overexpressed in ATLL and is associated with pERK expression. It correlates with an increased proliferation index, indicating an aggressive clinical course. EZH2 also correlates with SUZ12 and H3K27me3 co-expression, suggesting its PRC2-dependent catalytic activity through trimethylation. Additionally, EZH2 is overexpressed in most T-cell neoplasms, suggesting that EZH2 could function as an oncogenic protein in T-cell tumorigenesis. EZH2 and pERK could serve as potential therapeutic targets for treating aggressive ATLL. EZH2 could also be targeted in other T-cell neoplasms.

Assessment of Bcl-xL, TAX, and HBZ Gene Expression in Adult T cell Leukemia/Lymphoma Patients.

Adult T cell leukemia/lymphoma is a malignancy with a poor prognosis caused by human T lymphocyte virus type 1 (HTLV-1) infection. Tax and HBZ are two major viral proteins that may be involved in oncogenesis by disrupting apoptosis. Because Bcl-xL plays an integral role in the anti-apoptotic pathway, this study examines the interaction between host apoptosis and oncoproteins. We investigated 37 HTLV-1-infected individuals, including 18 asymptomatic and 19 adult T cell leukemia/lymphoma (ATLL) subjects. mRNA was extracted and converted to cDNA from peripheral blood mononuclear cells, and then gene expression was determined using TaqMan q-PCR. Moreover, the HTLV-1 proviral load (PVL) was also measured using a commercial absolute quantification kit (Novin Gene, Iran). Data analysis revealed that the mean of TAX, HBZ, and PVL was significantly higher among the study groups (ATLL and carrier groups p = .003, p = .000, and p = .002 respectively). There was no statistical difference in Bcl-xL gene expression between the study groups (p = .323). It is proposed that this anti-apoptotic pathway may not be directly involved in the development of ATLL lymphoma. Bcl-xL, TAX, HBZ gene expression, and PVL can be utilized as prognostic markers.

New Perspectives about Drug Candidates Targeting HTLV-1 and Related Diseases.

Among the human T-lymphotropic virus (HTLV) types, HTLV-1 is the most prevalent, and it has been linked to a spectrum of diseases, including HAM/TSP, ATLL, and hyperinfection syndrome or disseminated strongyloidiasis. There is currently no globally standard first-line treatment for HTLV-1 infection and its related diseases. To address this, a comprehensive review was conducted, analyzing 30 recent papers from databases PubMed, CAPES journals, and the Virtual Health Library (VHL). The studies encompassed a wide range of therapeutic approaches, including antiretrovirals, immunomodulators, antineoplastics, amino acids, antiparasitics, and even natural products and plant extracts. Notably, the category with the highest number of articles was related to drugs for the treatment of ATLL. Studies employing mogamulizumab as a new perspective for ATLL received greater attention in the last 5 years, demonstrating efficacy, safe use in the elderly, significant antitumor activity, and increased survival time for refractory patients. Concerning HAM/TSP, despite corticosteroid being recommended, a more randomized clinical trial is needed to support treatment other than corticoids. The study also included a comprehensive review of the drugs used to treat disseminated strongyloidiasis in co-infection with HTLV-1, including their administration form, in order to emphasize gaps and facilitate the development of other studies aiming at better-directed methodologies. Additionally, docking molecules and computer simulations show promise in identifying novel therapeutic targets and repurposing existing drugs. These advances are crucial in developing more effective and targeted treatments against HTLV-1 and its related diseases.

Human T-cell Lymphotropic Virus Type 1 (HTLV-1)-Associated Adult T-cell Leukemia/Lymphoma in a Patient Previously Treated for Strongyloidiasis.

Adult T-cell leukemia/lymphoma (ATLL) is a rare form of T-cell lymphoma with poor median survival time and limited response to chemotherapy. We present a 45-year-old female from Ghana with generalized body rash, hypercalcemia, lymphadenopathy, and lytic bone lesions. She had a history of strongyloidiasis, treated two years ago, and her serology was positive for the human T-cell lymphotropic virus type 1 (HTLV-1). Histopathology of cervical lymph node and abdominal rash biopsy revealed T-cell lymphoma. We present a literature review on the topic and the challenges of diagnosis. We emphasize the importance of considering HTLV-1-associated ATLL in patients who have been treated for strongyloidiasis in the past and are presenting with rash or lymphadenopathy.

A Textbook Case of Human T-lymphotropic Virus-1 (HTLV-1)-Induced Adult T-cell Leukemia Treated With Cyclophosphamide, Hydroxydaunorubicin, Oncovin, and Prednisone/Prednisolone (CHOP).

Human T-lymphotropic virus-1 (HTLV-I) is an enveloped, single-stranded RNA virus of the Retroviridae family. The virus causes two well-recognized disease associations: adult T-cell leukemia/lymphoma (ATL) and HTLV-I-associated myelopathy (HAM), also known as tropical spastic paraparesis (TSP). We report a case of HTLV-1-induced adult T-cell lymphoma/leukemia in a 45-year-old female who presented with complaints of swelling on the right side of her neck and rash on her upper and lower extremities and abdomen. The patient also had a history of strongyloidiasis infection and Crohn's disease. She was found to have hypercalcemia and multiple lytic lesions of the bone found on the imaging. She also tested positive for HTLV-1 and T cell-positive for cluster of differentiation (CD) 2, CD3, partial CD5, and minimal CD56, later confirmed by the bone marrow (BM) and skin punch biopsies. ATL is characterized by the clonal proliferation of CD4+ T cells containing randomly integrated HTLV-I provirus, often associated with T-cell receptor gene rearrangements. ATL, in its aggressive forms, has one of the poorest prognoses of non-Hodgkin lymphoma. It is essential to raise awareness of ATL, although further research and trials are needed to solidify the treatment options to prevent mortality.

Decoding dysregulated angiogenesis in HTLV-1 asymptomatic carriers compared to healthy individuals.

Human T-cell lymphotropic virus type 1 (HTLV-1) is the first identified human retrovirus responsible for two significant diseases: HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia/lymphoma (ATLL). Although the majority of infected individuals remain asymptomatic carriers, a small percentage may develop ATLL or HAM/TSP. In tumorigenesis, a crucial process is angiogenesis, which involves the formation of new blood vessels. However, the precise mechanism of HTLV-1 associated angiogenesis remains unclear. This study aims to investigate the gene regulation involved in the angiogenesis signaling pathway associated with HTLV-1 infection. The research enrolled 20 male participants, including asymptomatic carriers and healthy individuals. Blood samples were collected and screened using ELISA for HTLV-1 confirmation, and PCR was performed for both Tax and HBZ for validation. RNA extraction and cDNA synthesis were carried out, followed by RT-qPCR analysis targeting cellular genes involved in angiogenesis. Our findings indicate that gene expression related to angiogenesis was elevated in HTLV-1 ACs patients. However, the differences in gene expression of the analyzed genes, including HSP27, Paxillin, PDK1, PTEN, RAF1, SOS1, and VEGFR2 between ACs and healthy individuals were not statistically significant. This suggests that although angiogenesis-related genes may show increased expression in HTLV-1 infection, they might not be robust indicators of ATLL progression in asymptomatic carriers. The results of our study demonstrate that angiogenesis gene expression is altered in ACs of HTLV-1, indicating potential involvement of angiogenesis in the early stages before ATLL development. While we observed elevated angiogenesis gene expression in ACs, the lack of statistical significance between ACs and healthy individuals suggests that these gene markers may not be sufficient on their own to predict the development of ATLL in asymptomatic carriers.

Therapeutic approaches for HTLV-1-associated adult T-cell leukemia/lymphoma: a comprehensive review.

Adult T-cell leukemia/lymphoma (ATLL), an infrequent malignancy resultant from human T-cell lymphotropic virus type I (HTLV-1), exhibits a spectrum of phenotypes, encompassing acute, smoldering, lymphomatous, and chronic variants, each bearing distinct clinical presentations. The preponderant acute manifestation is characterized by hypercalcemia, systemic manifestations, organomegaly, and dermatological eruptions. Conversely, the chronic phenotype is typified by lymphocytosis and/or cutaneous eruptions, while smoldering ATLL assumes an asymptomatic course. Immunocompromise afflicts ATLL patients, heightening their vulnerability to opportunistic infections that frequently intricately intertwine with disease progression. Therefore, an early diagnosis is crucial to manage the disease appropriately. While conventional chemotherapeutic regimens have shown limited success, especially in acute and lymphoma types, recent studies suggest that allogeneic stem cell transplantation might enhance treatment results because it has shown promising outcomes in some patients. Novel therapeutics, such as interferon and monoclonal antibodies, have also shown promise, but more research is needed to confirm their efficacy. Moreover, the identification of biomarkers for ATLL and genetic changes in HTLV-1 infected cells has led to the development of targeted therapies that have shown remarkable success in clinical trials. These targeted therapies have the potential to offer a more personalized approach to the treatment of ATLL. The aim of our review is to elaborate on conventional and novel therapies and the efficiency of mentioned treatments.

Differential modulation of IL-4, IL-10, IL-17, and IFN-γ production mediated by IgG from Human T-lymphotropic virus-1 (HTLV-1) infected patients on healthy peripheral T (CD4+, CD8+, and γδ) and B cells.

Human T-lymphotropic virus 1 (HTLV-1) infected individuals remain as asymptomatic carriers (ACs) or can develop the chronic neurological disorder HTLV-1-associated myelopathy/Tropical Spastic Paraparesis (HAM/TSP) or the adult T-cell leukemia/lymphoma (ATLL), and the immunological mechanisms involved in this pathologies need to be elucidated. Recently, it has been demonstrated that induced or naturally developed IgG repertoires obtained from different groups of donors, grouped by immune status, can modulate human T and B cell functions. Here we aimed to evaluate if the IgG obtained from HTLV-1-infected ACs, HAM/TSP, and ATLL patients can differentially modulate the production of cytokines by human T and B cells. With this purpose, we cultured PBMCs with IgG purified from ACs, HAM/TSP, or ATLL donors and evaluated the frequency and intracellular cytokine production by flow cytometry. Our results indicate that IgG from HAM/TSP patients could induce an augment of IL-17-producing CD4+ T cells, reduce the frequency of IL-4-producing CD4+ T cells, increase IFN-γ-producing CD8+ T cells, and reduce IL-4-producing CD8+ T cells. IgG from ATLL could reduce the frequency of IL-4-producing CD4+ T cells, similarly to IgG from HAM/TSP /TSP, and could reduce the frequency of IFN-γ-producing γδT cells without influence on IL-17- and IL4-producing γδT and could reduce the frequency of IL-10- producing B cells. Finally, IgG from both HAM/TSP and ATLL patients could reduce the frequency of IFN-γ producing B cells. In conclusion, these results suggest that these preparations are active, partly overlapping in their effects, and able to elicit distinct effects on target populations.

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 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.

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.

Rigosertib is more potent than wortmannin and rapamycin against adult T-cell leukemia-lymphoma.

Human T lymphotropic virus type 1 (HTLV-1) infection can cause adult T-cell lymphoblastic leukemia (ATLL), an incurable, chemotherapy-resistant malignancy. In a quest for new therapeutic targets, our study sought to determine the levels of AKT, mTOR, and PI3K in ATLL MT-2 cells, HTLV-1 infected NIH/3T3 cells (Inf-3T3), and HTLV-1 infected patients (Carrier, HAM/TSP, and ATLL). Furthermore, the effects of rigosertib, wortmannin, and rapamycin on the PI3K/Akt/mTOR pathway to inhibit the proliferation of ATLL cells were examined. The results showed that mRNA expression of Akt/PI3K/mTOR was down-regulated in carrier, HAM/TSP, and ATLL patients, as well as MT-2, and Inf-3T3 cells, compared to the healthy individuals and untreated MT-2 and Inf-3T3 as controls. However, western blotting revealed an increase in the phosphorylated and activated forms of AKT and mTOR. Treating the cells with rapamycin, wortmannin, and rigosertib decreased the phosphorylated forms of Akt and mTOR and restored their mRNA expression levels. Using these inhibitors also significantly boosted the expression of the pro-apoptotic genes, Bax/Bcl-2 ratio as well as the expression of the tumor suppressor gene p53 in the MT-2 and Inf-3T3cells. Rigosertib was more potent than wortmannin and rapamycin in inducing sub-G1 and G2-M cell cycle arrest, as well as late apoptosis in the Inf-3T3 and MT-2 cells. It also synergized the cytotoxic effects of vincristine. These findings demonstrate that HTLV-1 downregulation of the mRNA level may occur as a negative feedback response to increased PI3K-Akt-mTOR phosphorylation by HTLV-1. Therefore, using rigosertib alone or in combination with common chemotherapy drugs may be beneficial in ATLL patients.

Mechanisms of Innate Immune Sensing of HTLV-1 and Viral Immune Evasion.

Human T lymphotropic virus-1 (HTLV-1) was the first identified oncoretrovirus, which infects and establishes a persistent infection in approximately 10-20 million people worldwide. Although only ~5% of infected individuals develop pathologies such as adult T-cell leukemia/lymphoma (ATLL) or a neuroinflammatory disorder termed HTLV-1-asssociated myelopathy/tropical spastic paraparesis (HAM/TSP), asymptomatic carriers are more susceptible to opportunistic infections. Furthermore, ATLL patients are severely immunosuppressed and prone to other malignancies and other infections. The HTLV-1 replication cycle provides ligands, mainly nucleic acids (RNA, RNA/DNA intermediates, ssDNA intermediates, and dsDNA), that are sensed by different pattern recognition receptors (PRRs) to trigger immune responses. However, the mechanisms of innate immune detection and immune responses to HTLV-1 infection are not well understood. In this review, we highlight the functional roles of different immune sensors in recognizing HTLV-1 infection in multiple cell types and the antiviral roles of host restriction factors in limiting persistent infection of HTLV-1. We also provide a comprehensive overview of intricate strategies employed by HTLV-1 to subvert the host innate immune response that may contribute to the development of HTLV-1-associated diseases. A more detailed understanding of HTLV-1-host pathogen interactions may inform novel strategies for HTLV-1 antivirals, vaccines, and treatments for ATLL or HAM/TSP.

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.

Rapid T-cell lymphoma progression associated with immune checkpoint inhibitors.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are widely used for multiple types of malignancies and are considered the fourth pillar in cancer treatment. Anti-programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab are approved for relapsed/refractory classical Hodgkin lymphoma. Nonetheless, two phase 2 trials for T-cell lymphoma were terminated because of hyperprogression after a single dose in some patients. AREAS COVERED: In this review, we summarize available information on the rapid progression of peripheral T-cell lymphoma including adult T-cell leukemia/lymphoma (ATLL). EXPERT OPINION: In the abovementioned two trials, disease subtypes in patients who experienced hyperprogression were mostly ATLL or angioimmunoblastic T-cell lymphoma. Possible hyperprogression mechanisms induced by PD-1 blockade are the compensatory upregulation of the expression of other checkpoints, altered expression of lymphoma-promoting growth factors, functional blockade of stromal PD-ligand 1 acting as a tumor suppressor, and unique immune environment in indolent ATLL. The differentiation between hyperprogression and pseudoprogression is practically essential. There are no established methods to predict hyperprogression before administration of an ICI. In the future, the progress of novel diagnostic modalities such as positron emission tomography with computed tomography and circulating tumor DNA is expected to facilitate early cancer detection.

Shikonin Induces ROS-Dependent Apoptosis Via Mitochondria Depolarization and ER Stress in Adult T Cell Leukemia/Lymphoma.

Adult T cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy that develops in some elderly human T-cell leukemia virus (HTVL-1) carriers. ATLL has a poor prognosis despite conventional and targeted therapies, and a new safe and efficient therapy is required. Here, we examined the anti-ATLL effect of Shikonin (SHK), a naphthoquinone derivative that has shown several anti-cancer activities. SHK induced apoptosis of ATLL cells accompanied by generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential, and induction of endoplasmic reticulum (ER) stress. Treatment with a ROS scavenger, N-acetylcysteine (NAC), blocked both loss of mitochondrial membrane potential and ER stress, and prevented apoptosis of ATLL cells, indicating that ROS is an upstream trigger of SHK-induced apoptosis of ATLL cells through disruption of the mitochondrial membrane potential and ER stress. In an ATLL xenografted mouse model, SHK treatment suppressed tumor growth without significant adverse effects. These results suggest that SHK could be a potent anti-reagent against ATLL.