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Treatment algorithm for adult T-cell leukemia-lymphoma (ATL) patients. ATL diagnosis is based on anti-HTLV-1 antibody positivity in the serum, the presence of mature T-cell malignancy, and the Southern blot detection of monoclonal integration of HTLV-1 proviral DNA in the tumor cells. ATL treatment is usually determined according to the clinical subtypes and prognostic factors. The presence of an aggressive-type ATL (acute, lymphoma and chronic types with poor prognostic factors) or indolent-type ATL (chronic and smoldering types without poor prognostic factors) is critical when making treatment decisions. Patients with an aggressive-type (acute, lymphoma and unfavorable chronic type) generally receive immediate combination chemotherapy or antiviral therapy with zidovudine and interferon-a (AZT ⁄ IFN), except for those with the lymphoma type. The international consensus meeting primarily recommends the VCAP-AMP-VECP regimen. Other therapeutic regimens include CHOP14, CHOP21, mEPOCH and ATL-G-CSF. The patients undergo further treatment with allogeneic hematopoietic stem cell transplantation, which is particularly effective in young patients with good performance statuses, and those who have achieved remission before transplantation. In Japan, patients with an indolent-type ATL without any skin lesions are usually followed up under a watchful waiting policy until the disease transforms to an aggressive type. Antiviral therapy is frequently performed for favorable chronic and smoldering ATL patients in nonJapanese nations, and skin directed therapy is applied for smoldering ATL with skin manifestations. allo-HSCT, allogeneic hematopoietic stem cell transplantation; ATL-G-CSF, combination chemotherapy consisting of vincristine, vindesine, doxorubicin, mitoxantrone, cyclophosphamide, etoposide, ranimustine, and prednisone with granulocyte-colony stimulating factor support; AZT ⁄ IFN, zidovudine and interferon-a; CHOP, cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP14 is performed every 2 weeks and CHOP21 is performed every 3 weeks); CR, complete remission; hyper CVAD, cyclophosphamide, vincristine, doxorubicin, and dexamethasone; MAC, myeloablative conditioning; mEPOCH, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) with modifications; PD, progressive disease; PR, partial remission; PS, performance status; RIC, reduced intensity conditioning; SD, stable disease; VCAP-AMP-VECP, vincristine, cyclophosphamide, doxorubicin and prednisone (VCAP)-doxorubicin, ranimustine and prednisone (AMP)-vindesine, etoposide, carboplatin and prednisone (VECP).
Source publication
Recent advances in treatment for adult T-cell leukemia-lymphoma (ATL) are reviewed herein. It is currently possible to select a therapeutic strategy for ATL and predict prognosis by classification of patients by clinical subtypes and clinicopathological factors. Although the overall survival (OS) of patients with ATL has increased marginally becaus...
Context in source publication
Context 1
... current treatment strategy for patients with ATL is shown in Figure 1. Treatment is based on the clinical subtype. Patients with aggressive ATL, such as acute, lymphoma or chronic types, with at least one poor prognostic factor should receive early chemotherapy. In the USA and Europe, antiviral therapy using AZT ⁄ IFN is the standard treatment for leuke- mic-type ATL. In Europe, chemotherapy is the first-line thera- py for lymphoma-type ATL, because OS with antiviral therapy alone is very short. (19) ...
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Elevated levels of soluble CD30 (sCD30) are linked with various T-cell neoplasms. However, the relationship between sCD30 levels and the development of adult T-cell leukemia (ATL) in human T-cell leukemia virus type 1 (HTLV-1) carriers remains to be clarified. We here investigated whether plasma sCD30 is associated with risk of ATL in a nested case...
Background
Human T-cell leukemia virus (HTLV-1) is a lymphotropic retrovirus associated to adult T cell leukemia (ATL) and to non-neoplastic inflammatory conditions affecting the central nervous system, lung or skin. The inflammatory disorders associated to HTLV-1 are mediated by different proinflammatory cytokines as IL-1α, IL-6, TNF-α. The releas...
Adult T-cell leukemia-lymphoma (ATL) is a mature T-cell malignancy associated with human T-cell leukemia virus type I (HTLV-1) infection. Japan is the most endemic country for HTLV-1 and ATL in the world. Recent nationwide studies of Japanese blood donors reported that HTLV-1 carriers spread from endemic areas to non-endemic areas. Therefore, the l...
Abstract Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell neoplasm caused by human T-cell leukemia virus type I (HTLV-I). Therapeutic interventions have not been associated with satisfactory outcomes. We showed that the porphyrin metabolic pathway preferentially accumulates the endogenous photosensitive metabolite, protoporphyrin IX (Pp...
Citations
... Given the unfavorable prognosis of ATLL, increasing the awareness of this disease is crucial. Moreover, recognizing the significance of preventing HTLV-1 infection in carriers and interrupting motherto-infant transmission is essential in eradicating ATLL [16]. ...
... This classification is useful for making decisions concerning treatment. According to the criteria used to diagnose ATL [8], the indolent subtypes (i.e., smoldering and favorable chronic) are usually managed with watchful waiting until acute crisis [10], and the aggressive subtypes (i.e., acute, lymphoma, and unfavorable chronic) are managed using a variety of intensive chemotherapies followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) depending on the age [11,12]. More recently, anti-CC chemokine receptor 4 (CCR4) monoclonal antibody (mAb) (mogamulizumab) [13,14] and lenalidomide [15] have also been used for treating relapsed or refractory ATL. ...
γδ T cells and natural killer (NK) cells have attracted much attention as promising effector cell subsets for adoptive transfer for use in the treatment of malignant and infectious diseases, because they exhibit potent cytotoxic activity against a variety of malignant tumors, as well as virus-infected cells, in a major histocompatibility complex (MHC)-unrestricted manner. In addition, γδ T cells and NK cells express a high level of CD16, a receptor required for antibody-dependent cellular cytotoxicity. Adult T-cell leukemia–lymphoma (ATL) is caused by human T-lymphotropic virus type I (HTLV-1) and is characterized by the proliferation of malignant peripheral CD4+ T cells. Although several treatments, such as chemotherapy, monoclonal antibodies, and allogeneic hematopoietic stem cell transplantation, are currently available, their efficacy is limited. In order to develop alternative therapeutic modalities, we considered the possibility of infusion therapy harnessing γδ T cells and NK cells expanded using a novel nitrogen-containing bisphosphonate prodrug (PTA) and interleukin (IL)-2/IL-18, and we examined the efficacy of the cell-based therapy for ATL in vitro. Peripheral blood samples were collected from 55 patients with ATL and peripheral blood mononuclear cells (PBMCs) were stimulated with PTA and IL-2/IL-18 for 11 days to expand γδ T cells and NK cells. To expand NK cells alone, CD3+ T-cell-depleted PBMCs were cultured with IL-2/IL-18 for 10 days. Subsequently, the expanded cells were examined for cytotoxicity against ATL cell lines in vitro. The proportion of γδ T cells in PBMCs was markedly low in elderly ATL patients. The median expansion rate of the γδ T cells was 1998-fold, and it was 12-fold for the NK cells, indicating that γδ T cells derived from ATL patients were efficiently expanded ex vivo, irrespective of aging and HTLV-1 infection status. Anti-CCR4 antibodies enhanced the cytotoxic activity of the γδ T cells and NK cells against HTLV-1-infected CCR4-expressing CD4+ T cells in an antibody concentration-dependent manner. Taken together, the adoptive transfer of γδ T cells and NK cells expanded with PTA/IL-2/IL-18 is a promising alternative therapy for ATL.
... A non-Hodgkin lymphoma with a biology comparable to T-ALL is T-lymphoblastic lymphoma (T-LLy). The human T cell lymphocytic virus type 1 (HTLV1) is the primary cause of the exceedingly aggressive blood malignancy known as adult T cell leukemia/lymphoma (ATLL) (8,9).T cell large granular lymphocytic leukemia (T-LGL) and T prolymphocytic leukemia (T-PLL) are two further uncommon types of T cell leukemia (10). The two main types of T cell lymphomas are cutaneous T cell lymphoma (CTCL) and peripheral T cell lymphoma (PTCL). ...
Melatonin, (N-acetyl-5-methoxytryptamine) an indoleamine exerts multifaced effects and regulates numerous cellular pathways and molecular targets associated with circadian rhythm, immune modulation, and seasonal reproduction including metabolic rewiring during T cell malignancy. T-cell malignancies encompass a group of hematological cancers characterized by the uncontrolled growth and proliferation of malignant T-cells. These cancer cells exhibit a distinct metabolic adaptation, a hallmark of cancer in general, as they rewire their metabolic pathways to meet the heightened energy requirements and biosynthesis necessary for malignancies is the Warburg effect, characterized by a shift towards glycolysis, even when oxygen is available. In addition, T-cell malignancies cause metabolic shift by inhibiting the enzyme pyruvate Dehydrogenase Kinase (PDK) which in turn results in increased acetyl CoA enzyme production and cellular glycolytic activity. Further, melatonin plays a modulatory role in the expression of essential transporters (Glut1, Glut2) responsible for nutrient uptake and metabolic rewiring, such as glucose and amino acid transporters in T-cells. This modulation significantly impacts the metabolic profile of T-cells, consequently affecting their differentiation. Furthermore, melatonin has been found to regulate the expression of critical signaling molecules involved in T-cell activations, such as CD38, and CD69. These molecules are integral to T-cell adhesion, signaling, and activation. This review aims to provide insights into the mechanism of melatonin's anticancer properties concerning metabolic rewiring during T-cell malignancy. The present review encompasses the involvement of oncogenic factors, the tumor microenvironment and metabolic alteration, hallmarks, metabolic reprogramming, and the anti-oncogenic/oncostatic impact of melatonin on various cancer cells. CITATION Rai S, Roy G and Hajam YA (2024) Melatonin: a modulator in metabolic rewiring in T-cell malignancies.
... A non-Hodgkin lymphoma with a biology comparable to T-ALL is T-lymphoblastic lymphoma (T-LLy). The human T cell lymphocytic virus type 1 (HTLV1) is the primary cause of the exceedingly aggressive blood malignancy known as adult T cell leukemia/lymphoma (ATLL) (8,9).T cell large granular lymphocytic leukemia (T-LGL) and T prolymphocytic leukemia (T-PLL) are two further uncommon types of T cell leukemia (10). The two main types of T cell lymphomas are cutaneous T cell lymphoma (CTCL) and peripheral T cell lymphoma (PTCL). ...
Melatonin, (N-acetyl-5-methoxytryptamine) an indoleamine exerts multifaced effects and regulates numerous cellular pathways and molecular targets associated with circadian rhythm, immune modulation, and seasonal reproduction including metabolic rewiring during T cell malignancy. T-cell malignancies encompass a group of hematological cancers characterized by the uncontrolled growth and proliferation of malignant T-cells. These cancer cells exhibit a distinct metabolic adaptation, a hallmark of cancer in general, as they rewire their metabolic pathways to meet the heightened energy requirements and biosynthesis necessary for malignancies is the Warburg effect, characterized by a shift towards glycolysis, even when oxygen is available. In addition, T-cell malignancies cause metabolic shift by inhibiting the enzyme pyruvate Dehydrogenase Kinase (PDK) which in turn results in increased acetyl CoA enzyme production and cellular glycolytic activity. Further, melatonin plays a modulatory role in the expression of essential transporters (Glut1, Glut2) responsible for nutrient uptake and metabolic rewiring, such as glucose and amino acid transporters in T-cells. This modulation significantly impacts the metabolic profile of T-cells, consequently affecting their differentiation. Furthermore, melatonin has been found to regulate the expression of critical signaling molecules involved in T-cell activations, such as CD38, and CD69. These molecules are integral to T-cell adhesion, signaling, and activation. This review aims to provide insights into the mechanism of melatonin’s anticancer properties concerning metabolic rewiring during T-cell malignancy. The present review encompasses the involvement of oncogenic factors, the tumor microenvironment and metabolic alteration, hallmarks, metabolic reprogramming, and the anti-oncogenic/oncostatic impact of melatonin on various cancer cells.
... In Japan, one of the areas with the highest occurrence of ATLL, chemotherapy is used with the association of several drugs such as Hiper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with high doses of methotrexate and cytarabine) and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOEP (CHOP + etoposide), but some of these drugs are not available outside Japan [31]. Antiviral therapy with zidovudine (AZT) and interferon-α (IFN) has been frequently applied for ATLL in Europe and the USA, but the mechanism of action of AZT/IFN has been partially elucidated [32]. ...
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.
... Currently, about 10-20 million people worldwide are infected with HTLV-1, and 1-10% of them will develop severe ATL or HAM/TSP diseases (Gessain et al., 1985;Hinuma et al., 1981;Pasquier et al., 2018). For the last years, ATL patients have been treated using chemotherapy-based approaches, but with very limited benefit as the median survival rate is only 8-10 months (Bazarbachi et al., 2011;Cook and Phillips, 2021;Utsunomiya et al., 2015). Improved survival is achieved by antiviral therapies combining zidovudine and interferon-alpha (Nasr et al., 2017), allogenic hematopoietic stem cell transplantation (Fuji et al., 2016), or the use of monoclonal antibodies targeting CC chemokine receptor 4 (CCR4), which is frequently expressed in ATL patient samples (Ishida et al., 2015;Yoshie et al., 2002). ...
Human T-cell leukemia virus type-1 (HTLV-1) is the first pathogenic retrovirus discovered in human. Although HTLV-1-induced diseases are well-characterized and linked to the encoded Tax-1 oncoprotein, there is currently no strategy to target Tax-1 functions with small molecules. Here, we analyzed the binding of Tax-1 to the human homolog of the drosophila discs large tumor suppressor (hDLG1/SAP97), a multi-domain scaffolding protein involved in Tax-1-transformation ability. We have solved the structures of the PDZ binding motif (PBM) of Tax-1 in complex with the PDZ1 and PDZ2 domains of hDLG1 and assessed the binding of 10 million molecules by virtual screening. Among the 19 experimentally confirmed compounds, one systematically inhibited the Tax-1-hDLG1 interaction in different biophysical and cellular assays, as well as HTLV-1 cell-to-cell transmission in a T-cell model. Thus, our work demonstrates that interactions involving Tax-1 PDZ-domains are amenable to small-molecule inhibition, which provides a framework for the design of targeted therapies for HTLV-1-induced diseases.
... (HTLV-II) were the first retroviruses discovered, respectively in 1980 [1] and 1982 [2]. They are responsible for adult T-cell leukemia/lymphoma (ATLL) [3], HTLV-associated myelopathy (HAM) [4] and inflammatory diseases such as uveitis, myositis and dermatitis [4]. HTLV in adult population is unevenly distributed worldwide: highly endemic in Japan, Caraibeans and several African areas while virtually absent in other regions [5,6]. ...
Background:
Diagnosis of Human T-cell Lymphotropic Virus (HTLV) types I and II infection requires sequencial testing with firstly a screening using an Enzyme immunoassay followed by a confirmatory test.
Objectives:
To compare the performances of the Alinity i rHTLV-I/II (Abbott®) and LIAISON® XL murex recHTLV-I/II serological screening tests to the ARCHITECT rHTLVI/II test followed if positive by HTLV BLOT 2.4, MP Diagnostics as the reference.
Study design:
119 serum samples from 92 known HTLV-I infected patients and 184 from uninfected patients with HTLV were analyzed in parallel with, Alinity i rHTLV-I/II, LIAISON® XL murex recHTLV-I/II and ARCHITECT rHTLVI/II.
Results:
Alinity i rHTLV-I/II and LIAISON® XL murex recHTLV-I/II exhibited a total agreement with ARCHITECT rHTLVI/II for both positive and negative samples. Both tests are suitable alternatives for HTLV screening.
... Currently, about 10-20 million people worldwide are infected with HTLV-1, and 1-10% of them will develop severe ATL or HAM/TSP diseases (Gessain et al., 1985;Hinuma et al., 1981;Pasquier et al., 2018). For the last years, ATL patients have been treated using chemotherapy-based approaches, but with very limited benefit as the median survival rate is only 8-10 months (Bazarbachi et al., 2011;Cook and Phillips, 2021;Utsunomiya et al., 2015). Improved survival is achieved by antiviral therapies combining zidovudine and interferon-alpha (Nasr et al., 2017), allogenic hematopoietic stem cell transplantation (Fuji et al., 2016), or the use of monoclonal antibodies targeting CC chemokine receptor 4 (CCR4), which is frequently expressed in ATL patient samples (Ishida et al., 2015;Yoshie et al., 2002). ...
Human T-cell leukemia virus type-1 (HTLV-1) is the first pathogenic retrovirus discovered in human. Although HTLV-1-induced diseases are well characterized and linked to the encoded Tax-1 oncoprotein, there is currently no strategy to target Tax-1 functions with small molecules. Here, we analysed the binding of Tax-1 to the human homolog of the drosophila discs large tumor suppressor (hDLG1/SAP97), a multi-domain scaffolding protein involved in Tax-1-transformation ability. We have solved the structures of the PDZ binding motif (PBM) of Tax-1 in complex with the PDZ1 and PDZ2 domains of hDLG1 and assessed the binding of 10 million molecules by virtual screening. Among the 19 experimentally confirmed compounds, one systematically inhibited the Tax-1-hDLG1 interaction in different biophysical and cellular assays, as well as HTLV-1 cell-to-cell transmission in a T-cell model. Thus, our work demonstrates that interactions involving Tax-1 PDZ-domains are amenable to small-molecule inhibition, which provides a framework for the design of targeted therapies for HTLV-1-induced diseases.
... However, these therapies can exhibit toxic side-effects with high concentration levels or long-term use. Treatment of ATLL involves the nucleoside reverse transcriptase inhibitor (NRTI) zidovudine (AZT) and interferonα as the standard first-line of care [5,6]. HAM/TSP is likewise difficult to treat. ...
Objectives
HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neuroinflammatory autoimmune disease characterized by high levels of infected immortalized T cells in circulation, which makes it difficult for antiretroviral (ART) drugs to work effectively. In previous studies, we established that Apigenin, a flavonoid, can exert immunomodulatory effects to reduce neuroinflammation. Flavonoids are natural ligands for the aryl hydrocarbon receptor (AhR), which is a ligand activated endogenous receptor involved in the xenobiotic response. Consequently, we tested Apigenin’s synergy in combination with ART against the survival of HTLV-1-infected cells.
Methods
First, we established a direct protein-protein interaction between Apigenin and AhR. We then demonstrated that Apigenin and its derivative VY-3-68 enter activated T cells, drive nuclear shuttling of AhR, and modulate its signaling both at RNA and protein level.
Results
In HTLV-1 producing cells with high AhR expression, Apigenin cooperates with ARTs such as Lopinavir (LPN) and Zidovudine (AZT), to impart cytotoxicity by exhibiting a major shift in IC 50 that was reversed upon AhR knockdown. Mechanistically, Apigenin treatment led to an overall downregulation of NF-κB and several other pro-cancer genes involved in survival.
Conclusions
This study suggest the potential combinatorial use of Apigenin with current first-line antiretrovirals for the benefit of patients affected by HTLV-1 associated pathologies.
... Given the association with HTLV-1, current therapeutic regimens take advantage of anti-viral compounds, such as zidovudine and IFN-α, in addition to allogeneic HSC transplantation [307]. The standard combination of chemotherapeutics for aggressive ATL is vincristine, cyclophosphamide, doxorubicin, and prednisone [308]. ...
Dysregulation of sphingolipid metabolism plays a complex role in hematological malignancies, beginning with the first historical link between sphingolipids and apoptosis discovered in HL-60 leukemic cells. Numerous manuscripts have reviewed the field including the early discoveries that jumpstarted the studies. Many studies discussed here support a role for sphingolipids, such as ceramide, in combinatorial therapeutic regimens to enhance anti-leukemic effects and reduce resistance to standard therapies. Additionally, inhibitors of specific nodes of the sphingolipid pathway, such as sphingosine kinase inhibitors, significantly reduce leukemic cell survival in various types of leukemias. Acid ceramidase inhibitors have also shown promising results in acute myeloid leukemia. As the field moves rapidly, here we aim to expand the body of literature discussed in previously published reviews by focusing on advances reported in the latter part of the last decade.
