Human T-cell leukaemia virus type I and adult T-cell leukaemia-lymphoma

doi:10.1016/S1470-2045(14)70202-5

The Lancet Oncology

Volume 15, Issue 11, October 2014, Pages e517-e526

https://doi.org/10.1016/S1470-2045(14)70202-5 Get rights and content

Summary

Adult T-cell leukaemia-lymphoma (ATL) is a malignancy of peripheral T lymphocytes caused by human T-lymphotropic virus type I (HTLV-1), and its prognosis is poor. There are an estimated 5 million to 20 million HTLV-1 infected individuals worldwide; their lifetime risk of developing ATL is 3–5%, and high HTLV-1 proviral loads have been shown to be an independent risk factor. Recent advances in the treatment of ATL are the introduction of treatment targeted against CC chemokine receptor 4 (CCR4), which is abundantly expressed on most ATL cells, and allogeneic haemopoietic stem-cell transplantation for aggressive ATL. Promising outcomes are also reported with early intervention for indolent ATL with interferon α and zidovudine. Clinical trials should incorporate a validated prognostic index to assess the results, because of the difficulties associated with undertaking large-scale trials and significant diversity of clinical features with ATL, even in the same clinical subtypes (acute, lymphoma, chronic, and smoldering).

Introduction

Adult T-cell leukaemia-lymphoma (ATL) is a malignancy of peripheral T lymphocytes caused by human T-lymphotropic virus type I (HTLV-1), and its prognosis is poor compared with other aggressive non-Hodgkin lymphomas. The clinical entity of ATL was first proposed in 1977 as a distinct T-cell neoplasm frequently observed in southwestern Japan, and the RNA retrovirus HTLV-1 was subsequently isolated as the causative virus.1, 2 HTLV-1 also causes HTLV-1-associated myelopathy-tropical spastic paraparesis (HAM-TSP), a chronic inflammatory disease of the CNS characterised by slowly progressive spastic paraparesis, lower limb sensory disturbance, and bladder or bowel dysfunction.3, 4 Differences in the immune response to HTLV-1 in infected individuals, which are at least partially dependent on the HLA haplotypes—ie, low immune responders to HTLV-1 infected cells are at risk of ATL but high immune responders to HTLV-1 infected cells are at risk of HAM-TSP—have been proposed as the reasons why the same virus causes two distinctive diseases, one a malignant disease and the other an inflammatory disease.5, 6 By contrast, a less efficient response by cytotoxic T cells against HTLV-1 is reported to be the cause of risk of HAM-TSP since it causes a higher proviral load and higher antigen expression that activates and expands antigen-specific T-cell responses, followed by induction of large amount of proinflammatory cytokines and chemokines.⁷ In HTLV-1 carriers in Japan, the lifetime risk of ATL is estimated 3–5% (5–7% for men and 2–4% for women) and of HAM-TSP is 0·25%.8, 9

The clinical course of ATL is very heterogeneous, and the Japan Clinical Oncology Group (JCOG) has proposed four clinical subtypes (acute, lymphoma, chronic, and smoldering types) based on the prognostic factors, clinical features, and the natural history of the disease. Acute, lymphoma, and unfavourable chronic types are considered to be aggressive ATLs, and favourable chronic and smoldering types are indolent ATLs.10, 11

In this Review, we discuss the epidemiology of HTLV-1, transmission of HTLV-1 and its prevention, recent advances in the oncogenesis and pathophysiology of ATL, identification of HTLV-1 carriers at high risk of development of ATL, and the clinical features, treatment, and prognostic index of this disease.

Section snippets

Epidemiology of HTLV-1

HTLV-1 is endemic in southwestern Japan, the Caribbean, intertropical Africa, the Middle East, South America, and Papua New Guinea, and the prevalence of patients with ATL and HAM-TSP has been linked to the distribution of HTLV-1.¹²

The origin of HTLV-1 is considered to be primate T-cell lymphotropic virus (PTLV) in African non-human primates. It migrated within a simian reservoir towards Asia, and evolved into simian T-cell leukaemia virus type-I (STLV-1). This STLV-1 lineage spread to Japan

Transmission and prevention of HTLV-1

Clustering of HTLV-1 carriers was reported in family members of patients with ATL soon after the identification of the virus, suggesting that this virus is transmitted by close contact within the family.21, 22 Three major HTLV-1 transmission routes are mother-to-child, sexual intercourse, and blood transfusions containing cellular components–ie, HTLV-1 infected lymphocytes.²³

Transmission via transfusion has been almost eliminated through viral screening of donated blood, which has been done

Oncogenesis and pathophysiology of ATL

HTLV-1-infected cells express the virus protein Tax, which has various cellular functions including activation of NF-κB, Akt signalling, and cyclin-dependent kinases, and silencing of P53 function. Tax has been considered to play a key part in the oncogenesis of ATL in the early stages, because Tax could immortalise T lymphocytes in vitro,²⁵ and transgenic mice which expressed Tax showed oncogenic capabilities.²⁶ However, because Tax is a target for the host cytotoxic T cells, there is some

Identification of high-risk HTLV-1 carriers for development of ATL

The lifetime risk of development of ATL in HTLV-1 carriers is only 3–5%. Currently, we have no established method to predict the risk of progression to ATL in HTLV-1 carriers, and no information is available about whether a routine clinical check up of HTLV-1 carriers is useful for the early detection of progression and whether it ultimately improves outcomes. To delineate the risk factors for development of ATL in HTLV-1 carriers will be beneficial. HTLV-1 proviral load was significantly

Clinical features of ATL

Patients with ATL exhibit diverse clinical features such as generalised lymphadenopathy, skin lesions, hepatosplenomegaly, leucocytosis with increased abnormal lymphocytes showing cerebriform or flower-like nuclei or with increased neutrophils, hypercalcaemia, and frequent complication of opportunistic infections due to Pneumocystis jirovecci, candida, cytomegalovirus, and Strongyloides stercoralis. ATL cells characteristically express CD3, CD4, CD25, CCR4, and FOXP3 on their surface, and

Aggressive ATL: chemotherapy

The treatment strategies for aggressive ATL and indolent ATL were developed on the basis of those for other malignant lymphomas such as diffuse large B-cell lymphoma and chronic lymphocytic leukaemia, respectively (panel).

An international consensus meeting⁴⁶ recommended first-line treatment for ATL with chemotherapies such as the VCAP-AMP-VECP regimen, which is a sequential combination chemotherapy consisting of vincristine, cyclophosphamide, doxorubicin, and prednisolone (VCAP); doxorubicin,

Prognostic index for ATL

The huge diversity in the clinical course of ATL, even for the acute and lymphoma types, and the absence of a validated prognostic index specific to this cohort of patients, has made it difficult to assess the results of single group studies and to consider risk-adapted treatment strategies. A prognostic index for acute and lymphoma type ATL was developed using a retrospective analysis of medical records from 807 patients in Japan.⁵¹ Multivariable analysis showed that the variables of Ann Arbor

Discussion

The therapeutic outcome of patients with ATL has been improved by the introduction of multiagent chemotherapy, antiviral therapies, allogeneic HSCT, and advances in supportive care. However, the outlook for these patients is still poor. The reasons for the difficulties associated with doing clinical trials of this disease include its rarity and scattered distribution worldwide. The main differences of therapeutic approach between Japan and other countries are frequent incorporation of

Search strategy and selection criteria

References for this Review were identified by searching PubMed for English-language articles with the terms “ATL or ATLL”, “human T-cell lymphotropic virus type I or HTLV-1”, and “HAM or TSP” up to February, 2014. Articles were also identified through searches of the authors' own files. The final reference list was generated on the basis of originality and relevance to the broad scope of this Review.

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Reprogramming of pyrimidine nucleotide metabolism supports vigorous cell proliferation of normal and malignant T cells
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Adult T-cell leukemia/lymphoma (ATL) is triggered by infection with human T-cell lymphotropic virus-1 (HTLV-1). Here, we describe the reprogramming of pyrimidine biosynthesis in both normal T cells and ATL cells through regulation of uridine-cytidine kinase 2 (UCK2), which supports vigorous proliferation. UCK2 catalyzes the monophosphorylation of cytidine/uridine and their analogues during pyrimidine biosynthesis and drug metabolism. We found that UCK2 was overexpressed aberrantly in HTLV-1–infected T cells but not in normal T cells. T-cell activation via T-cell receptor (TCR) signaling induced expression of UCK2 in normal T cells. Somatic alterations and epigenetic modifications in ATL cells activate TCR signaling. Therefore, we believe that expression of UCK2 in HTLV-1–infected cells is induced by dysregulated TCR signaling. Recently, we established azacitidine-resistant (AZA-R) cells showing absent expression of UCK2. AZA-R cells proliferated normally in vitro, whereas UCK2 knockdown inhibited ATL cell growth. Although uridine and cytidine accumulated in AZA-R cells, possibly because of dysfunction of pyrimidine salvage biosynthesis induced by loss of UCK2 expression, the amount of UTP and CTP was almost the same as in parental cells. Furthermore, AZA-R cells were more susceptible to an inhibitor of dihydroorotic acid dehydrogenase, which performs the rate-limiting enzyme of de novo pyrimidine nucleotide biosynthesis, and more resistant to dipyridamole, an inhibitor of pyrimidine salvage biosynthesis, suggesting that AZA-R cells adapt to UCK2 loss by increasing de novo pyrimidine nucleotide biosynthesis. Taken together, the data suggest that fine-tuning pyrimidine biosynthesis supports vigorous cell proliferation of both normal T cells and ATL cells.
Potential applications of ferroptosis inducers and regulatory molecules in hematological malignancy therapy
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Ferroptosis, a novel form of iron-dependent cell death, has emerged as a potential avenue for promoting tumor cell death by causing cell membrane rupture and the accumulation of lipid peroxides (LPO) in the cell. Since its discovery in 2012, extensive research has been conducted to explore the mechanism of ferroptosis inducers, including erastin, sulfasalazine, and sorafenib. These compounds inhibit system XC-, while Ras-selective lethal small molecule 3 (RSL3) and FION2 specifically target GPX4 to promote ferroptosis. Therefore, targeting ferroptosis presents a promising therapeutic approach for malignant tumors. While the study of ferroptosis in solid tumors has made significant progress, there is limited information available on its role in hematological tumors. This review aims to summarize the molecular mechanisms of ferroptosis inducers and discuss their clinical applications in hematological malignancies. Furthermore, the identification of non-coding RNAs (ncRNAs) and genes that regulate key molecules in the ferroptosis pathway could provide new targets and establish a molecular theoretical foundation for exploring novel ferroptosis inducers in hematological malignancies.
Illuminating (HTLV-1)-induced adult T-cell leukemia/lymphoma transcriptomic signature: A systems virology approach
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Adult T-cell leukemia/lymphoma (ATLL) is a poor prognosis malignancy of peripheral T-cells caused by human T-cell leukemia virus type 1 (HTLV-1). The low survival rates observed in the patients are the result of the lack of sufficient knowledge about the disease pathogenesis.
In the present study, we first identified differentially expressed genes in ATLL patients and the cellular signaling pathways affected by them. Then, genes of these pathways were subjected to more comprehensive evaluations, including WGCNA and module validation studies on five external datasets. Finally, potential biomarkers were selected for qRT-PCR validation.
Thirteen signaling pathways, including Apoptosis, Human T-cell leukemia virus 1 infection, IL-17 signaling pathway, pathways in cancer, T cell receptor signaling pathway, Th1 and Th2 cell differentiation, and seven others were selected for deeper investigations. Results of our in-depth bioinformatics evaluations, highlighted pathways related to regulation of immune responses, T-cell receptor and activation, regulation of cell signaling receptors and messengers, Wnt signaling pathway, and apoptosis as key players in ATLL pathogenesis. MAPK3, PIK3CD, KRAS, NFKB1, TNF, PLCB3, PLCB2, PLCB1, MAPK11, JUN, ITPR1, ADCY1, GNAQ, ADCY3, ADCY4, CHEK1, CCND1, SOS2, BAX, FOS and GNA12 were identified as possible biomarkers. Upregulation of ADCY1 and ADCY3 genes was confirmed via qRT-PCR.
In this study, we performed a deep bioinformatic examination on a limited set of genes with high probabilities of involvement in the pathogenesis of ATLL. Our results highlighted signaling pathways and genes with potential key roles in disease formation and resistance against current treatment strategies. Further studies are required to test the possible benefits of highlighted genes as biomarkers and targets of treatment.
GPCR signaling contributes to immune characteristics of microenvironment and process of EBV-induced lymphomagenesis
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Epstein-Barr virus (EBV) is the oncogenic driver of multiple cancers. However, the underlying mechanism of virus-cancer immunological interaction during disease pathogenesis remains largely elusive. Here we reported the first comprehensive proteogenomic characterization of natural killer/T-cell lymphoma (NKTCL), a representative disease model to study EBV-induced lymphomagenesis, incorporating genomic, transcriptomic, and in-depth proteomic data. Our multi-omics analysis of NKTCL revealed that EBV gene pattern correlated with immune-related oncogenic signaling. Single-cell transcriptome further delineated the tumor microenvironment as immune-inflamed, -deficient, and -desert phenotypes, in association with different setpoints of cancer-immunity cycle. EBV interacted with transcriptional factors to provoke GPCR interactome (GPCRome) reprogramming. Enhanced expression of chemokine receptor-1 (CCR1) on malignant and immunosuppressive cells modulated virus-cancer interaction on microenvironment. Therapeutic targeting CCR1 showed promising efficacy with EBV eradication, T-cell activation, and lymphoma cell killing in NKTCL organoid. Collectively, our study identified a previously unknown GPCR-mediated malignant progression and translated sensors of viral molecules into EBV-specific anti-cancer therapeutics.
Novel Zn(II)-complex with hybrid chalcone-thiosemicarbazone ligand: Synthesis, characterization, and inhibitory effect on HTLV-1-infected MT-2 leukemia cells
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Chalcone and thiosemicarbazone have attracted attention due to their easy synthetic procedure and high success in the development of antiviral and antitumor, however, there are few biological data on the evaluation of chalcone-thiosemicarbazone hybrids and their complexation with metal ions. In this sense, the present work reports the synthesis and characterization of the hybrid (Z)-2-((E)-3-(4-chlorophenyl)-1-phenylallylidene)hydrazine-1-carbothioamide (CTCl) and its Zn(II)-complex (CTCl-Zn). The compounds were cell-based evaluated in terms of cytotoxicity against human T-cell lymphotropic virus type 1 (HTLV-1) infected leukemia cells (MT-2) and the experimental data were correlated with molecular docking calculations. The ligand and Zn(II)-complex were easily synthesized with a good yield - 57% and 79%, respectively. The dynamic of E/Z isomers with respect to the imine bond configuration of CTCl was evidenced by ¹H NMR experiments in DMSO‑d₆, while the X-ray diffraction of CTCl-Zn showed that Zn(II) ion is tetracoordinated to two ligands in a bidentate mode and the metal ion lies on an intermediate geometry between the see-saw and trigonal pyramid. The ligand and complex exhibited low toxicity and the Zn(II)-complex is more cytotoxic than the ligand, with the corresponding IC₅₀ value of 30.01 and 47.06 μM. Both compounds had a pro-apoptotic effect without the release of reactive oxygen species (ROS) and they can interact with DNA via minor grooves driven by van der Waals forces.
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ReviewHuman T-cell leukaemia virus type I and adult T-cell leukaemia-lymphoma

Summary

Introduction

Section snippets

Epidemiology of HTLV-1

Transmission and prevention of HTLV-1

Oncogenesis and pathophysiology of ATL

Identification of high-risk HTLV-1 carriers for development of ATL

Clinical features of ATL

Aggressive ATL: chemotherapy

Prognostic index for ATL

Discussion

Search strategy and selection criteria

Blood

Lancet

Lancet

Blood

Blood

Blood

Cancer Cell

Blood

Blood

Blood

Blood

Cancer Lett

Blood

Blood

Blood

Blood

Blood

Blood

Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma

Proc Natl Acad Sci USA

Human T-lymphotropic virus type 1 (HTLV-1) and regulatory T cells in HTLV-1-associated neuroinflammatory disease

Viruses

The influence of HLA class I alleles and heterozygosity on the outcome of human T cell lymphotropic virus type I infection

J Immunol

Adult T-cell leukemia: a review of epidemiological evidence

Front Microbiol

The risk of development of HTLV-I-associated myelopathy/tropical spastic paraparesis among persons infected with HTLV-I

J Acquir Immune Defic Syndr

Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87)

Br J Haematol

Chemotherapy of ATL

Global epidemiology of HTLV-I infection and associated diseases

Oncogene

Dating the origin of the African human T-cell lymphotropic virus type-i (HTLV-I) subtypes

Mol Biol Evol

An HTLV-I vaccine: why, how, for whom?

AIDS Res Hum Retroviruses

Epidemiological aspects and world distribution of HTLV-1 infection

Front Microbiol

Current prevalence of HTLV-1 in Japan as determined by screening of blood donors

J Med Virol

Human T-lymphotropic virus type 1 and type 2 seroprevalence, incidence, and residual transfusion risk among blood donors in Brazil during 2007–2009

AIDS Res Hum Retroviruses

Blood safety strategies for human T-cell lymphotropic virus in Europe

Vox Sang

Prevalence of human T-lymphotropic virus type 1 and 2 infection in Sweden

Scand J Infect Dis

The outcome of donor screening for human T-cell lymphotropic virus infection in The Netherlands

Vox Sang

Epidemiological analysis of the distribution of antibody to adult T-cell leukemia-virus-associated antigen: possible horizontal transmission of adult T-cell leukemia virus

Gann

High incidence of human type-C retrovirus (HTLV) in family members of a HTLV-positive Japanese T-cell leukemia patient

Proc Natl Acad Sci USA

A retrospective study on transmission of adult T cell leukemia virus by blood transfusion: seroconversion in recipients

Vox Sang

Mother-to-child transmission of human T-cell lymphotropic virus type 1

Pediatr Infect Dis J

Animal models for human T-lymphotropic virus type 1 (HTLV-1) infection and transformation

Oncogene

Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation

Nat Rev Cancer

Review
Human T-cell leukaemia virus type I and adult T-cell leukaemia-lymphoma