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1.
Immunol Cell Biol ; 102(5): 298-301, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38606590

RESUMEN

Epigenetic modifications, particularly through methylation of DNA packaging histones, play a pivotal role in controlling gene expression. Aberrant patterns of histone methylation have been associated with the development and progression of hematological malignancies. Unraveling the impact of aberrant histone marks on gene expression and leukemogenesis has spurred a concerted effort to develop clinically effective epigenetic therapies. In malignancies associated with the accumulation of histone H3 lysine trimethylation (H3K27me3), one such intervention involves preventing the deposition of this repressive histone mark by inhibiting the histone-modifying enzymes EZH1 and EZH2. While inhibition of EZH1/2 has demonstrated efficacy in both preclinical studies and clinical trials in various cancers, studies delineating the dynamic effect of EZH1/2 inhibition on H3K27me3 and disease relapse in clinical samples are lacking. In a recent publication, Yamagishi et al. explore how responses of a patient with adult T-cell leukemia/lymphoma to valemetostat, an EZH1/2 inhibitor, are associated with changes in H3K27me3, chromatin accessibility and gene expression, and how these changes can be circumvented in relapsed disease.


Asunto(s)
Epigénesis Genética , Histonas , Leucemia-Linfoma de Células T del Adulto , Animales , Humanos , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Histonas/metabolismo , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/patología , Complejo Represivo Polycomb 2/metabolismo , Complejo Represivo Polycomb 2/genética
2.
J Med Virol ; 96(9): e29898, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39221490

RESUMEN

The active form of vitamin D (VD) exerts hormonal effects by regulating the expression of genes involved in T-cell activity, cell differentiation, and proliferation. Human T-cell leukemia virus type 1 (HTLV-1) is a causative agent of life-threatening diseases, adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy (HAM). Among ATL patients, hypercalcemia is one of the most serious complications due to bone resorption. In this study, wild-type mice administered UV-irradiated HTLV-1-infected cells showed up to 47% decrease of plasma VD level compared with untreated mice. To clarify the effect of HTLV-1 on plasma VD level, 315 samples registered in nationwide cohort study on ATL onset were measured. The VD level in HAM (14.98 ± 8.5 ng/mL) was significantly lower than those in asymptomatic carriers and ATL (p < 0.05). Upon comparing the VD levels in ATL stratified by disease subtypes, acute ATL showed a lower level (15.81 ± 12.0 ng/mL) than chronic and smoldering types (p < 0.05). In the longitudinal observation, VD levels were significantly higher in untreated spontaneous remission cases than in ATL progression cases, in which the VD levels decreased approximately 40% after onset. In cases of relapse after transplantation, the plasma VD level dropped to 38.7% of the pre-relapse level, while in cases of complete remission, the VD level increased with improvement of the performance status. Taken together, these results suggest that plasma VD level is a potential indicator for the onset and relapse of HTLV-1-associated diseases.


Asunto(s)
Infecciones por HTLV-I , Virus Linfotrópico T Tipo 1 Humano , Vitamina D , Humanos , Animales , Vitamina D/sangre , Virus Linfotrópico T Tipo 1 Humano/patogenicidad , Ratones , Femenino , Infecciones por HTLV-I/sangre , Infecciones por HTLV-I/virología , Masculino , Persona de Mediana Edad , Leucemia-Linfoma de Células T del Adulto/sangre , Leucemia-Linfoma de Células T del Adulto/virología , Adulto , Anciano , Modelos Animales de Enfermedad , Paraparesia Espástica Tropical/sangre , Paraparesia Espástica Tropical/virología , Estudios de Cohortes
3.
Cytokine ; 182: 156710, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39089216

RESUMEN

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.


Asunto(s)
Infecciones por HTLV-I , Virus Linfotrópico T Tipo 1 Humano , Interleucina-17 , Leucemia-Linfoma de Células T del Adulto , Paraparesia Espástica Tropical , Humanos , Infecciones por HTLV-I/inmunología , Infecciones por HTLV-I/virología , Virus Linfotrópico T Tipo 1 Humano/inmunología , Interleucina-17/inmunología , Interleucina-17/metabolismo , Leucemia-Linfoma de Células T del Adulto/virología , Leucemia-Linfoma de Células T del Adulto/inmunología , Paraparesia Espástica Tropical/inmunología , Paraparesia Espástica Tropical/virología
4.
Eur J Haematol ; 2024 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-39239903

RESUMEN

OBJECTIVES: The role of glycogen synthase kinase (GSK)-3ß in adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1) is paradoxical and enigmatic. Here, we investigated the role of GSK-3ß and its potential as a therapeutic target for ATL. METHODS: Cell proliferation/survival, cell cycle, apoptosis, and reactive oxygen species (ROS) generation were examined using the WST-8 assay, flow cytometry, and Hoechst 33342 staining, respectively. Expression of GSK-3ß and cell cycle/death-related proteins, and survival signals was analyzed using RT-PCR, immunofluorescence staining, and immunoblotting. RESULTS: HTLV-1-infected T-cell lines showed nuclear accumulation of GSK-3ß. GSK-3ß knockdown and its inhibition with 9-ING-41 and LY2090314 suppressed cell proliferation/survival. 9-ING-41 induced G2/M arrest by enhancing the expression of γH2AX, p53, p21, and p27, and suppressing the expression of CDK1, cyclin A/B, and c-Myc. It induced caspase-mediated apoptosis by decreasing the expression of Bcl-xL, Mcl-1, XIAP, c-IAP1/2, and survivin, and increasing the expression of Bak and Bax. 9-ING-41 also induced ferroptosis and necroptosis, promoted JNK phosphorylation, and suppressed IKKγ and JunB expression. It inhibited the phosphorylation of IκBα, Akt, and STAT3/5, induced ROS production, and reduced glycolysis-derived lactate levels. CONCLUSION: GSK-3ß functions as an oncogene in ATL and could be a potential therapeutic target.

5.
Eur J Haematol ; 113(1): 99-109, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38558052

RESUMEN

OBJECTIVES: We aimed to determine the role of dihydroorotate dehydrogenase (DHODH) in pathogenesis of adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1) and the effects of its inhibition on the de novo pyrimidine biosynthesis pathway. METHODS: Cell proliferation, viability, cycle, and apoptosis were analyzed using WST-8 assays, flow cytometry, and Hoechst 33342 staining. To elucidate the molecular mechanisms involved in the anti-ATL effects of DHODH knockdown and inhibition, RT-PCR and immunoblotting were conducted. RESULTS: HTLV-1-infected T-cell lines aberrantly expressed DHODH. Viral infection and the oncoprotein, Tax, enhanced DHODH expression, while knockdown of DHODH decreased HTLV-1-infected T-cell growth. In addition, BAY2402234, a DHODH inhibitor, exerted an anti-proliferative effect, which was reversed by uridine supplementation. BAY2402234 induced DNA damage and S phase arrest by downregulating c-Myc, CDK2, and cyclin A and upregulating p53 and cyclin E. It also induced caspase-mediated apoptosis by the upregulation of pro-apoptotic and downregulation of anti-apoptotic proteins. Furthermore, BAY2402234 induced caspase-independent ferroptosis and necroptosis. It decreased phosphorylation of IKK, IκBα, PTEN, Akt, and its downstream targets, suggesting that inhibition of NF-κB and Akt signaling is involved in its anti-ATL action. CONCLUSION: These findings highlight DHODH as a potential therapeutic target for treating ATL.


Asunto(s)
Apoptosis , Proliferación Celular , Dihidroorotato Deshidrogenasa , Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Humanos , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/etiología , Leucemia-Linfoma de Células T del Adulto/metabolismo , Leucemia-Linfoma de Células T del Adulto/patología , Leucemia-Linfoma de Células T del Adulto/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Transducción de Señal/efectos de los fármacos , Terapia Molecular Dirigida , Pirimidinas/farmacología , Técnicas de Silenciamiento del Gen , Supervivencia Celular/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , FN-kappa B/metabolismo
6.
Hepatol Res ; 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38770705

RESUMEN

We report a case of fulminant hepatitis in a hepatitis B surface antigen (HBsAg)-positive patient with aggressive adult T-cell leukemia-lymphoma who received monotherapy with an anti-CCR4 monoclonal antibody, mogamulizumab, with decreased hepatitis B virus (HBV)- DNA levels by entecavir prophylaxis. Although HBV reactivation-related hepatitis was considered in the differential diagnosis, the patient did not meet the conventional criteria for HBV reactivation and was finally diagnosed with drug-induced hepatitis. Considering that the immunoenhancing effects of mogamulizumab can lead to HBV reactivation-related hepatitis in HBsAg-positive patients, we should differentiate drug-induced hepatitis from HBV reactivation, especially in patients receiving immunomodulatory drugs, if HBV-DNA levels are reduced by antiviral prophylaxis.

7.
Mol Ther ; 31(7): 2266-2285, 2023 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-36934299

RESUMEN

The human T cell leukemia virus type 1 (HTLV-1) is a pathogenic retrovirus that persists as a provirus in the genome of infected cells and can lead to adult T cell leukemia (ATL). Worldwide, more than 10 million people are infected and approximately 5% of these individuals will develop ATL, a highly aggressive cancer that is currently incurable. In the last years, genome editing tools have emerged as promising antiviral agents. In this proof-of-concept study, we use substrate-linked directed evolution (SLiDE) to engineer Cre-derived site-specific recombinases to excise the HTLV-1 proviral genome from infected cells. We identified a conserved loxP-like sequence (loxHTLV) present in the long terminal repeats of the majority of virus isolates. After 181 cycles of SLiDE, we isolated a designer-recombinase (designated RecHTLV), which efficiently recombines the loxHTLV sequence in bacteria and human cells with high specificity. Expression of RecHTLV in human Jurkat T cells resulted in antiviral activity when challenged with an HTLV-1 infection. Moreover, expression of RecHTLV in chronically infected SP cells led to the excision of HTLV-1 proviral DNA. Our data suggest that recombinase-mediated excision of the HTLV-1 provirus represents a promising approach to reduce proviral load in HTLV-1-infected individuals, potentially preventing the development of HTLV-1-associated diseases.


Asunto(s)
Virus Linfotrópico T Tipo 1 Humano , Paraparesia Espástica Tropical , Adulto , Humanos , Virus Linfotrópico T Tipo 1 Humano/genética , Paraparesia Espástica Tropical/tratamiento farmacológico , Paraparesia Espástica Tropical/genética , Provirus/genética , Antivirales
8.
Proc Natl Acad Sci U S A ; 118(10)2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33649200

RESUMEN

Constitutive NF-κB activation (NF-κBCA) confers survival and proliferation advantages to cancer cells and frequently occurs in T/B cell malignancies including adult T cell leukemia (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1). Counterintuitively, NF-κBCA by the HTLV-1 transactivator/oncoprotein Tax induces a senescence response, and HTLV-1 infections in culture mostly result in senescence or cell-cycle arrest due to NF-κBCA How NF-κBCA induces senescence, and how ATL cells maintain NF-κBCA and avert senescence, remain unclear. Here we report that NF-κBCA by Tax increases R-loop accumulation and DNA double-strand breaks, leading to senescence. R-loop reduction via RNase H1 overexpression, and short hairpin RNA silencing of two transcription-coupled nucleotide excision repair (TC-NER) endonucleases that are critical for R-loop excision-Xeroderma pigmentosum F (XPF) and XPG-attenuate Tax senescence, enabling HTLV-1-infected cells to proliferate. Our data indicate that ATL cells are often deficient in XPF, XPG, or both and are hypersensitive to ultraviolet irradiation. This TC-NER deficiency is found in all ATL types. Finally, ATL cells accumulate R-loops in abundance. Thus, TC-NER deficits are positively selected during HTLV-1 infection because they facilitate the outgrowth of infected cells initially and aid the proliferation of ATL cells with NF-κBCA later. We suggest that TC-NER deficits and excess R-loop accumulation represent specific vulnerabilities that may be targeted for ATL treatment.


Asunto(s)
Daño del ADN , Reparación del ADN , ADN de Neoplasias/metabolismo , Productos del Gen tax/metabolismo , Virus Linfotrópico T Tipo 1 Humano/metabolismo , Leucemia-Linfoma de Células T del Adulto/metabolismo , FN-kappa B/metabolismo , Proteínas de Neoplasias/metabolismo , ADN de Neoplasias/genética , Productos del Gen tax/genética , Células HeLa , Virus Linfotrópico T Tipo 1 Humano/genética , Humanos , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/virología , FN-kappa B/genética , Proteínas de Neoplasias/genética
9.
Medicina (Kaunas) ; 60(6)2024 May 26.
Artículo en Inglés | MEDLINE | ID: mdl-38929489

RESUMEN

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.


Asunto(s)
Leucemia-Linfoma de Células T del Adulto , Humanos , Femenino , Leucemia-Linfoma de Células T del Adulto/mortalidad , Leucemia-Linfoma de Células T del Adulto/terapia , Leucemia-Linfoma de Células T del Adulto/epidemiología , Leucemia-Linfoma de Células T del Adulto/diagnóstico , Masculino , Adulto , Persona de Mediana Edad , Rumanía/epidemiología , Estudios Prospectivos , Virus Linfotrópico T Tipo 1 Humano , Infecciones por HTLV-I/mortalidad , Infecciones por HTLV-I/complicaciones , Anciano , Análisis de Supervivencia , Enfermedades Endémicas , Pronóstico
10.
Rinsho Ketsueki ; 65(2): 84-89, 2024.
Artículo en Japonés | MEDLINE | ID: mdl-38448003

RESUMEN

A 63-year-old man with adult T-cell leukemia-lymphoma underwent allogeneic bone marrow transplantation from an HLA-matched unrelated donor. On day 17 after transplantation, chest computed tomography (CT) showed nodules in the lower lobes of both lungs, and invasive pulmonary aspergillosis (IPA) was suspected. Treatment with liposomal amphotericin B was started, and improvement of infectious lesions was confirmed with CT on day 28. The antifungal agent was changed to voriconazole on day 52 because of progressive renal dysfunction. Disorders of consciousness and paralysis of the left upper and lower extremities developed on day 61. Brain CT showed subcortical hemorrhage in the right parietal and occipital lobes, and the patient died on day 62. An autopsy revealed filamentous fungi, suspected to be Aspergillus, in the pulmonary nodules and a ruptured cerebral aneurysm. Although IPA occurs in 10% of transplant recipients, vigilant monitoring for mycotic cerebral aneurysms is required to prevent hematogenous dissemination of Aspergillus, which is associated with a high mortality rate.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Aneurisma Intracraneal , Leucemia-Linfoma de Células T del Adulto , Linfoma , Adulto , Masculino , Humanos , Persona de Mediana Edad , Aneurisma Intracraneal/complicaciones , Aneurisma Intracraneal/terapia , Leucemia-Linfoma de Células T del Adulto/complicaciones , Leucemia-Linfoma de Células T del Adulto/terapia , Trasplante de Médula Ósea
11.
Rinsho Ketsueki ; 65(7): 628-632, 2024.
Artículo en Japonés | MEDLINE | ID: mdl-39098012

RESUMEN

A 62-year-old woman with adult T-cell leukemia/lymphoma (ATL) received umbilical cord blood transplantation (CBT) in first complete remission. However, relapse of ATL was detected on day 74 post-transplantation, as evidenced by the rapid growth of lymphoma cells in peripheral blood and an increase in soluble interleukin-2 receptor (sIL2R) levels. Discontinuation of immunosuppressant therapy alone did not improve ATL findings, but treatment with lenalidomide caused lymphoma cells to disappear from the peripheral blood and sIL2R levels to return to normal. Pancytopenia was observed as a lenalidomide-associated adverse effect, but lymphocyte counts were not reduced. The patient was judged to be in complete remission based on results of Southern blot analysis and human T-cell leukemia virus 1 (HTLV-1)-infected cell analysis using flow cytometry (HAS-Flow). Flow cytometric analysis of peripheral blood and FISH analysis of X and Y chromosomes revealed that the therapeutic effect of lenalidomide was associated with an increase in the number of donor-derived peripheral natural killer cells. ATL relapse was not observed at 13 months into lenalidomide treatment. Our results suggest that lenalidomide is an effective option for the treatment of post-transplant relapsed ATL.


Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical , Lenalidomida , Leucemia-Linfoma de Células T del Adulto , Recurrencia , Inducción de Remisión , Humanos , Lenalidomida/administración & dosificación , Lenalidomida/uso terapéutico , Leucemia-Linfoma de Células T del Adulto/terapia , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Femenino , Persona de Mediana Edad , Talidomida/análogos & derivados , Talidomida/uso terapéutico
12.
Crit Rev Clin Lab Sci ; 60(3): 189-211, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36593730

RESUMEN

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.


Asunto(s)
Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto , Linfoma , Paraparesia Espástica Tropical , Adulto , Humanos , Virus Linfotrópico T Tipo 1 Humano/genética , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/patología , Virulencia , Paraparesia Espástica Tropical/patología , Carcinogénesis , Transformación Celular Neoplásica
13.
Cancer Immunol Immunother ; 72(4): 929-944, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36181532

RESUMEN

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.


Asunto(s)
Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto , Adulto , Humanos , Leucemia-Linfoma de Células T del Adulto/metabolismo , Leucemia-Linfoma de Células T del Adulto/patología , Herpesvirus Humano 3 , Linfocitos T Citotóxicos , Vacunación
14.
Mod Pathol ; 36(8): 100169, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-36997002

RESUMEN

Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell tumor caused by human T-lymphotropic virus type 1 (HTLV-1). The typical ATLL immunophenotypes are described in the 2017 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues (positive: CD2, CD3, CD5, CD4, and CD25; negative: CD7, CD8, and cytotoxic markers; and partially positive: CD30, CCR4, and FOXP3). However, limited studies are available on the expression of these markers, and their mutual relationship remains unknown. Furthermore, the expression status of novel markers associated with T-cell lymphomas, including Th1 markers (T-bet and CXCR3), Th2 markers (GATA3 and CCR4), T follicular helper markers (BCL6, PD1, and ICOS), and T-cell receptor (TCR) markers, and their clinicopathologic significance is unclear. In this study, we performed >20 immunohistochemical stains in 117 ATLL cases to determine the comprehensive immunophenotypic profile of ATLL, which were compared on the basis of clinicopathologic factors, including morphologic variants (pleomorphic vs anaplastic), biopsy locations, treatments, Shimoyama classification-based clinical subtype, and overall survival. CD3+/CD4+/CD25+/CCR4+ was considered a typical immunophenotype of ATLL, but approximately 20% of cases did not conform to this pattern. Simultaneously, the following new findings were obtained: (1) most cases were negative for TCR-ß and TCR-δ (104 cases, 88.9%), indicating the usefulness of negative conversion of TCR expression to provide differentiation from other T-cell tumors; (2) the positivity of CD30 and CD15 and the negativity of FOXP3 and CD3 were significantly associated with anaplastic morphology; and (3) atypical cases, such as T follicular helper marker-positive (12 cases, 10.3%) and cytotoxic molecule-positive cases (3 cases, 2.6%), were identified. No single markers could predict the overall survival among patients with acute/lymphoma subtypes of ATLL. The results of this study illustrate the diversity of ATLL phenotypes. In T-cell tumors occurring in HTLV-1 carriers, the possibility of ATLL should not be eliminated even when the tumor exhibits an atypical phenotype, and the confirmation of HTLV-1 in the tissue is recommended.


Asunto(s)
Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto , Linfoma de Células T , Linfoma , Adulto , Humanos , Virus Linfotrópico T Tipo 1 Humano/genética , Factores de Transcripción Forkhead
15.
Hematol Oncol ; 41(3): 389-395, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-36513602

RESUMEN

Patients with recurrent adult T-cell leukemia/lymphoma (ATL) after allogeneic hematopoietic cell transplantation (allo-HCT) have a dismal prognosis. We retrospectively evaluated the safety and efficacy of lenalidomide (LEN) in 11 consecutive patients with recurrent ATL after allo-HCT. The median time from allo-HCT to ATL recurrence was 111 days (range, 20-1476), and that from allo-HCT to the initiation of LEN was 162 days (range, 43-1560). The median initial daily dose of LEN was 10 mg (range, 5-25), and the median duration of LEN treatment was 37 days (range, 3-1078). Three patients (27%) achieved complete response and two (18%) achieved partial response (PR). The rates of complete or PR according to the involved site were 57% for skin and 50% for nodal or extranodal lesions. With a median follow-up of 1033 days (range, 601-1465) among survivors, the 1-year probability of overall survival (OS) after ATL recurrence was 55%. Grade ≥3 toxicities included cytopenia (n = 4), superficial vein thrombosis (n = 1), and deep vein thrombosis (n = 1). Graft-versus-host disease (GVHD) newly developed in five patients (45%) and worsened in four patients (36%). The median duration from the initiation of LEN to GVHD onset or worsening was 5 days (range, 1-9). GVHD was manageable in all patients. Seven patients received mogamulizumab (MOG) for recurrent ATL before LEN treatment. The overall response rates to LEN were 57% in patients who had previously received MOG and 25% in those who had not. The 1-year probabilities of OS after recurrent ATL were 71% in patients who had previously received MOG and 25% in those who had not. Although cytopenia and GVHD are common among patients with recurrent ATL after allo-HCT, LEN may improve survival. Administering MOG before LEN may augment treatment efficacy in the allo-HCT population.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma de Células T del Adulto , Linfoma , Adulto , Humanos , Lenalidomida/uso terapéutico , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/patología , Estudios Retrospectivos , Recurrencia , Enfermedad Injerto contra Huésped/etiología
16.
Virol J ; 20(1): 118, 2023 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-37287047

RESUMEN

BACKGROUND: ATLL (Adult T-Cell Leukemia/Lymphoma) is an aggressive hematological malignancy. This T-cell non-Hodgkin lymphoma, caused by the human T-cell leukemia virus type 1 (HTLV-1), is challenging to treat. There is no known treatment for ATLL as of yet. However, it is recommended to use Zidovudine and Interferon Alfa-based regimens (AZT/IFN), chemotherapy, and stem cell transplant. This study aims to review the outcome of patients with different subtypes of ATLL treated with Zidovudine and Interferon Alfa-based regimens. METHODS: A systematic search was carried out for articles evaluating outcomes of ATLL treatment by AZT/IFN agents on human subjects from January 1, 2004, until July 1, 2022. Researchers assessed all studies regarding the topic, followed by extracting the data. A random-effects model was used in the meta-analyses. RESULTS: We obtained fifteen articles on the AZT/IFN treatment of 1101 ATLL patients. The response rate of the AZT/IFN regimen yielded an OR of 67% [95% CI: 0.50; 0.80], a CR of 33% [95% CI: 0.24; 0.44], and a PR of 31% [95% CI: 0.24; 0.39] among individuals who received this regimen at any point during their treatment. Our subgroup analyses' findings demonstrated that patients who received front-line and combined AZT/IFN therapy responded better than those who received AZT/IFN alone. It is significant to note that patients with indolent subtypes of disease had considerably higher response rates than individuals with aggressive disease. CONCLUSION: IFN/AZT combined with chemotherapy regimens is an effective treatment for ATLL patients, and its use in the early stages of the disease may result in a greater response rate.


Asunto(s)
Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto , Linfoma , Adulto , Humanos , Zidovudina/uso terapéutico , Interferón-alfa/uso terapéutico , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Linfoma/tratamiento farmacológico
17.
J Am Acad Dermatol ; 88(5): 965-980, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36041557

RESUMEN

Viral-induced cutaneous T-cell lymphomas are an uncommon group of lymphoproliferative disorders characterized by a viral infection of T and natural killer (NK) cells. This group of cutaneous T-cell lymphomas is more commonly encountered in Asians and Native Americans from Central and South America compared with Western populations. Viral-associated lymphoproliferative disorders include a spectrum of entities that range from nonneoplastic lesions, such as chronic active Epstein-Barr virus infection and infective dermatitis to malignant diseases, such as extranodal NK/T-cell lymphoma, hydroa vacciniforme-like T-cell lymphoma, and adult T-cell leukemia/lymphoma. This review article will focus on hydroa vacciniforme-like lymphoproliferative disorder, extranodal NK/T-cell lymphoma, adult T-cell leukemia/lymphoma, lymphomatoid granulomatosis, and Epstein-Barr virus-positive mucocutaneous ulcers. We will review the pathogenesis of these conditions and the challenges of making a timely diagnosis in early-stage disease and discuss the common clinicopathologic manifestations, mutational landscape, and approaches to treat these highly aggressive and frequently lethal types of lymphoma.


Asunto(s)
Trastornos Linfoproliferativos , Enfermedades de la Piel , Educación Médica Continua , Trastornos Linfoproliferativos/patología , Trastornos Linfoproliferativos/terapia , Trastornos Linfoproliferativos/virología , Enfermedades de la Piel/patología , Enfermedades de la Piel/terapia , Enfermedades de la Piel/virología , Infecciones por Virus de Epstein-Barr , Linfoma Cutáneo de Células T/patología , Linfoma Cutáneo de Células T/terapia , Linfoma Cutáneo de Células T/virología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Neoplasias Cutáneas/virología , Hidroa Vacciniforme/patología , Hidroa Vacciniforme/terapia , Leucemia-Linfoma de Células T del Adulto/patología , Leucemia-Linfoma de Células T del Adulto/terapia , Granulomatosis Linfomatoide/patología , Granulomatosis Linfomatoide/terapia
18.
Curr Treat Options Oncol ; 24(8): 948-964, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37300656

RESUMEN

OPINION STATEMENT: Adult T-cell leukemia/lymphoma (ATL) is a rare, aggressive subtype of peripheral T-cell lymphoma developing after many years of chronic, asymptomatic infection with the retrovirus human T-cell lymphotropic virus type 1 (HTLV-1). HTLV-1 is endemic to certain geographic areas of the world, and primary infection generally occurs in infancy through mother-to-child transmission via breastfeeding. In less than 5% of infected individuals, a decades-long pathogenic process culminates in the development of ATL. Aggressive subtypes of ATL are life-threatening and challenging to treat, with median overall survival typically less than 1 year in the absence of allogeneic hematopoietic cell transplantation (alloHCT). Owing to the rarity of this illness, prospective large-scale clinical trials have been challenging to perform, and treatment recommendations are largely founded upon limited evidence. Herein, we review the current therapeutic options for ATL, providing a broad literature overview of the foremost clinical trials and reports of this disease. We emphasize our own treatment paradigm, which is broadly based upon disease subtype, patient fitness, and intent to perform alloHCT. Finally, we highlight recent advances in understanding ATL disease biology and important ongoing clinical trials that we foresee as informative and potentially practice-changing.


Asunto(s)
Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto , Linfoma , Adulto , Humanos , Femenino , Leucemia-Linfoma de Células T del Adulto/diagnóstico , Leucemia-Linfoma de Células T del Adulto/etiología , Leucemia-Linfoma de Células T del Adulto/terapia , Estudios Prospectivos , Transmisión Vertical de Enfermedad Infecciosa
19.
Jpn J Clin Oncol ; 53(12): 1104-1111, 2023 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-37592900

RESUMEN

Adult T-cell leukemia-lymphoma is defined as peripheral T-cell lymphoma caused by the human T-cell leukemia virus type I. Adult T-cell leukemia-lymphoma is classified into indolent (favorable chronic or smoldering) or aggressive (acute, lymphoma or unfavorable chronic) types. This review discusses the therapeutic developments for patients with adult T-cell leukemia-lymphoma and unmet issues in treating adult T-cell leukemia-lymphoma. For indolent adult T-cell leukemia-lymphoma, a watchful waiting strategy is recommended until the disease progresses to aggressive adult T-cell leukemia-lymphoma. For aggressive adult T-cell leukemia-lymphoma, multi-agent chemotherapy with or without allogeneic hematopoietic stem cell transplantation has been recommended. However, many patients with adult T-cell leukemia-lymphoma relapse, and their prognosis is poor. Recently, novel agents, including mogamulizumab, lenalidomide, brentuximab vedotin, tucidinostat and valemetostat, have been approved for patients with relapsed or refractory aggressive adult T-cell leukemia-lymphoma, and the combination of mogamulizumab with multi-agent chemotherapy or brentuximab vedotin with cyclophosphamide, doxorubicin and prednisone has been approved for patients with untreated aggressive adult T-cell leukemia-lymphoma in Japan. Importantly, the aging of patients with adult T-cell leukemia-lymphoma has recently been reported, and no standard of care for elderly patients with adult T-cell leukemia-lymphoma has been established. New evidence must be obtained from prospective clinical trials to improve the prognosis of patients with adult T-cell leukemia-lymphoma.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma de Células T del Adulto , Adulto , Humanos , Anciano , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Brentuximab Vedotina/uso terapéutico , Estudios Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/uso terapéutico
20.
Biol Pharm Bull ; 46(9): 1269-1276, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37661406

RESUMEN

Adult T-cell leukemia/lymphoma (ATL) is a hematopoietic malignancy with a poor prognosis that develops in approximately 5% of human T-cell leukemia virus type 1 (HTLV-1) carriers. Cyclin-dependent kinase 9 (CDK9), together with Cyclin T, forms a transcription elongation factor, positive transcription elongation factor b (P-TEFb). P-TEFb promotes transcriptional elongation by phosphorylating the second serine (Ser2) of the seven amino acid repeat sequence in the C-terminal domain of RNA polymerase II (RNAP II). CDK9 inhibitors suppress cell proliferation by inducing apoptosis in chronic lymphocytic leukemia and breast cancer but there are no reports on autophagy of CDK9 inhibitors. Here, we investigated the effect of LY2857785, a novel CDK9 selective inhibitor, on cell death in ATL-related cell lines in vitro, freshly isolated cells from ATL patients ex vivo, and on ATL tumor xenografts in NOD/SCID mice in vivo. LY2857785 significantly reduced cell viability and induced apoptosis, as shown by annexin V-positive cells, cleaved poly(ADP-ribose) polymerase (PARP), and cleaved caspase-3, and suppressed the levels of anti-apoptotic protein myeloid cell leukemia-1 (MCL-1). LY2857785 decreased RNAP II Ser2 phosphorylation and downstream c-Myc protein levels. Interestingly, LY2857785 also increased microtubule-associated proteins 1A/1B light chain 3B (LC3)-II binding to autophagosome membranes. Furthermore, LY2857785 decreased the viability of freshly isolated ATL cells and induced apoptosis. Finally, LY2857785 significantly decreased the growth of ATL tumor xenografts. These results suggest that LY2857785 induces cell death of ATL cells by MCL-1-dependent apoptosis and autophagy and has anti-tumor activity.


Asunto(s)
Neoplasias de la Mama , Leucemia-Linfoma de Células T del Adulto , Linfoma , Ratones , Adulto , Animales , Humanos , Femenino , Ratones Endogámicos NOD , Ratones SCID , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Factor B de Elongación Transcripcional Positiva , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Inhibidores de Proteínas Quinasas , Apoptosis , Autofagia , Quinasa 9 Dependiente de la Ciclina
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