Basic zipper protein (HBZ): biomarcador diagnóstico y de seguimiento de leucemia/linfoma T del adulto / Basic zipper protein ( HBZ ) : diagnostic and follow - up biomarker of adult T - cell leukemia/lymphoma

Introducción: El virus linfotrópico de células T humanas tipo 1 es el retrovirus causal de la leucemia-linfoma de células T. Su escaso diagnóstico en fases agudas hace que encontrar un biomarcador acertado para conocer el desarrollo de la leucemia sea de interés clínico y científico. Objetivo: Presentar la proteína basic zipper protein como marcador diagnóstico y de seguimiento al tratamiento de la leucemia-linfoma de células T. Métodos: Se consultó material académico en diferentes bases de datos científicas tales como PubMed, Springerlink, Proquest y Sciencedirect. Se tuvieron en cuenta criterios como datos, efectividad en la identificación y amplificación de basic zipper protein, reconocimiento de las fases del virus linfotrópico de células T, epidemiología y mecanismos moleculares en la patogenia del virus. Análisis y síntesis de la información: La basic zipper protein es una proteína del virus linfotrópico de células T indispensable para el proceso de leucemogénesis, capaz de interactuar con factores endógenos del huésped, lo que la convierte en marcador de la enfermedad. Conclusiones: La basic zipper protein cuenta con características que la perfilan para ser el biomarcador con mayor predicción de la enfermedad por su estabilidad e importancia en la leucemogénesis. Además, el nivel de ARNm de la basic zipper protein es mayor en leucemia-linfoma de células T.

Introduction: Human T-cell lymphotropic virus type 1 is the retrovirus that causes T-cell leukemia-lymphoma. Its scarce diagnosis in acute phases means that finding an accurate biomarker to determine the development of leukemia is of clinical and scientific interest. Objective: To present the basic zipper protein as a diagnostic and follow-up marker for treatment of T-cell leukemia-lymphoma. Methods: Academic material was consulted in different scientific databases such as PubMed, Springerlink, Proquest and Sciencedirect. Criteria such as: data, effectiveness in the identification and amplification of basic zipper protein, recognition of the phases of the T-cell lymphotropic virus, epidemiology and molecular mechanisms in the pathogenesis of the virus were taken into account. Analysis and synthesis of the information: The basic zipper protein is a protein of the T-cell lymphotropic virus essential for the leukemogenesis process, capable of interacting with endogenous factors of the host, which makes it a marker of the disease. Conclusions: The Basic zipper protein has characteristics that outline it to be the biomarker with the highest prediction of the disease due to its stability and importance in leukemogenesis. In addition, the mRNA level of the basic zipper protein is higher in T-cell leukemia-lymphoma.

Effects of interferon inducible protein 16 (IFI16) on viral protein and pro-inflammatory cytokine ex-pression in human T-cell leukemia virus type 1 (HTLV-1)-positive T cells / 中华微生物学和免疫学杂志

Objective To investigate the effects of interferon inducible protein 16 (IFI16), a cy-tosolic DNA sensor, on the expression of human T-cell leukemia virus type 1 (HTLV-1) proteins and pro-in-flammatory cytokines in adult HTLV-1-positive T cells. Methods IFI16 expression in different HTLV-1-positive T cell lines was detected by immunoblot assay. Specific siRNA targeting the IFI16 gene was con-structed and the gene silencing efficiency was detected by immunoblot assay. Expression of HTLV-1 Tax pro-tein at mRNA and protein levels was respectively detected by real-time PCR and immunoblot assay after knocking down the expression of IFI16 in HTLV-1-positive T cells with siRNA. Expression of interferon ( IFN)-α, IFN-γ, tumor necrosis factor ( TNF )-α, Tax and Env were detected by real-time PCR. Re-sults Compared with the HTLV-1-negative T cell line Jurkat, IFI16 expression was enhanced in the HTLV-1-positive T cell lines MT2, MT4 and C8166. Tax expression was increased, while that of IFN-α, IFN-γand TNF-α was decreased in MT2 and MT4 cells after silencing the expression of IFI16 with siRNA. Con-clusions IFI16 expression was increased in HTLV-1-positive MT2 and MT4 cells. Meanwhile, IFI16 pro-moted the production of interferon and pro-inflammatory cytokines and inhibited the expression of HTLV-1 proteins.

Effects of interferon inducible protein 16 (IFI16) on viral protein and pro-inflammatory cytokine expression in human T-cell leukemia virus type 1 (HTLV-1)-positive T cells / 中华微生物学和免疫学杂志

Objective@#To investigate the effects of interferon inducible protein 16 (IFI16), a cytosolic DNA sensor, on the expression of human T-cell leukemia virus type 1 (HTLV-1) proteins and pro-inflammatory cytokines in adult HTLV-1-positive T cells.@*Methods@#IFI16 expression in different HTLV-1-positive T cell lines was detected by immunoblot assay. Specific siRNA targeting the IFI16 gene was constructed and the gene silencing efficiency was detected by immunoblot assay. Expression of HTLV-1 Tax protein at mRNA and protein levels was respectively detected by real-time PCR and immunoblot assay after knocking down the expression of IFI16 in HTLV-1-positive T cells with siRNA. Expression of interferon (IFN)-α, IFN-γ, tumor necrosis factor (TNF)-α, Tax and Env were detected by real-time PCR.@*Results@#Compared with the HTLV-1-negative T cell line Jurkat, IFI16 expression was enhanced in the HTLV-1-positive T cell lines MT2, MT4 and C8166. Tax expression was increased, while that of IFN-α, IFN-γ and TNF-α was decreased in MT2 and MT4 cells after silencing the expression of IFI16 with siRNA.@*Conclusions@#IFI16 expression was increased in HTLV-1-positive MT2 and MT4 cells. Meanwhile, IFI16 promoted the production of interferon and pro-inflammatory cytokines and inhibited the expression of HTLV-1 proteins.

Adult T-cell leukemia/lymphoma and acquired immunodeficiency syndrome - CD4+ T-cell malignancy in CD4+ T-cell deficient status: A paradox

CD4 counts along with viral loads are important parameters in the monitoring of human immunodeficiency virus (HIV) infection. Human T-cell lymphotropic virus type I (HTLV-I) is known to be an etiological agent for adult T-cell leukemia/lymphoma (ATLL). Coinfection of HTLV-I and HIV is well known in regions with high seroprevalence, and there is no published data in the Indian scenario. We present an interesting case of occurrence of CD4+ T-cell proliferation in a known beta thalassemia major with acquired HIV seropositivity accompanied by simultaneously increasing CD4+ counts and viral loads. Further workup revealed ATLL with an underlying HTLV infection.

Adult T-cell leukemia/lymphoma treatment in Bahia, Brazil

Abstract Background: Adult T-cell leukemia/lymphoma is a peripheral disease associated with human T-cell lymphotropic virus type 1. Treatment is carried out according to clinical type with watchful waiting being recommended for less aggressive types. Aggressive adult T-cell leukemia/lymphoma is generally treated with chemotherapy and/or antivirals. The objective of this study was to correlate the survival of patients diagnosed in Bahia, Brazil, with the therapeutic approaches employed and to evaluate what issues existed in their treatment processes. Methods: Eighty-three adult T-cell leukemia/lymphoma patients (26 smoldering, 23 chronic, 16 acute, 13 lymphoma and five primary cutaneous tumoral) with available data were included in this study. Results: Complete response was achieved in seven smoldering patients with symptomatic treatment, in two with chronic disease using antivirals/chemotherapy, in one with acute disease using antivirals and in one lymphoma using the LSG15 regimen [vincristine, cyclophosphamide, doxorubicin, and prednisolone (VCAP); doxorubicin, ranimustine, and prednisolone (AMP); and vindesine, etoposide, carboplatin, and prednisolone (VECP)]. Smoldering patients who received symptomatic treatment presented longer survival. Favorable chronic patients treated with antivirals presented longer survival compared to the unfavorable subtype. However, for the acute form, first-line chemotherapy was better, albeit without significance, than antivirals. Only one of the patients with lymphoma and primary cutaneous tumors responded. Conclusions: Watchful waiting associated with phototherapy represents the best option for smoldering adult T-cell leukemia/lymphoma with survival in Bahia being superior to that described in Japan. There was a trend of better results with zidovudine/interferon-alpha in favorable chronic disease. Excellent results were achieved in the lymphoma type treated with the LSG15 protocol. Patients are diagnosed late probably due to lack of knowledge of adult T-cell leukemia/lymphoma by primary healthcare doctors and a Brazilian treatment protocol needs to be established.

Prolonged lymphocytosis as the first manifestation of Hodgkin-like adult T-cell leukemia/lymphoma

Abstract Hodgkin-like ATLL is a rare variant of adult T-cell leukemia/lymphoma (ATLL), a disease caused by human T-cell lymphotropic virus type-1 (HTLV-1). At admission, a 46-year-old female presented with lymphadenomegaly, lymphocytosis, slight elevation of LDH blood level, and acid-alcohol resistant bacilli in sputum and was being treated for pulmonary tuberculosis (Tb). She had lymphocytosis in the previous 20 months. Serology for HTLV-1 was positive. Lymph node was infiltrated by medium-sized lymphocytes with scattered Hodgkin and Reed-Sternberg-like cells CD30+, CS1-4+, and CD79a+. Background cells were CD4+ and CD25+. A clinical diagnosis of favorable chronic ATLL was given. She was treated with chemotherapy but later progressed to acute ATLL and ultimately died. Hodgkin-like ATLL should be considered in the histological differential diagnosis with Hodgkin lymphoma since treatment and prognosis of these diseases are distinct. It is also important to search for HTLV-1 infection in patients with unexplained prolonged lymphocytosis.

Adult T-cell leukemia/lymphoma / Leucemia/linfoma de células T do adulto

Summary Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature CD4+ T-cells caused by human T-cell lymphotropic virus type 1 (HTLV-1). Twenty million people are believed to be infected throughout the world, mostly in Japan, Africa, the Caribbean, and South America, particularly in Brazil and Peru. ATL affects about 5% of infected individuals and is classified in the following clinical forms: acute, lymphoma, primary cutaneous tumoral, chronic (favorable and unfavorable), and smoldering (leukemic and non-leukemic). Although it is considered an aggressive disease, there are cases with a long progression. We emphasize the importance of clinical classification as an indispensable element for evaluating prognosis and appropriate therapeutic approach. Since several cases have been published in Brazil and this disease is still poorly known, we decided to make a review paper for dissemination of clinical, hematological and pathological aspects, diagnosis, and therapy. The best way to reduce the occurrence of ATL would be halting the transmission of the virus through breastfeeding.

Resumo A leucemia/linfoma de células T do adulto (LLcTA) é uma neoplasia de células T maduras CD4+ causada pelo vírus linfotrópico para células T humanas tipo 1 (HTLV-1). Acredita-se que existem cerca de 20 milhões de pessoas infectadas em todo o mundo, principalmente no Japão, na África, no Caribe e na América do Sul, particularmen te no Brasil e no Peru. A LLcTA acomete cerca de 5% dos indivíduos infectados e classifica-se nas seguintes formas clínicas: aguda, linfomatosa, tumoral primária de pele, crônica (favorável e desfavorável) e indolente (leucêmica e não leucêmica). Embora seja considerada uma doença agressiva, há casos com longa evolução. Salientamos a importância da classificação clínica como elemento im prescindível para avaliação do prognóstico e conduta terapêutica adequada. Como já foram publicados vários casos no Brasil e essa doença ainda é pouco conhecida, decidimos fazer um trabalho de revisão para divulgar os seus aspectos clínicos, hematológicos, anatomopatológi cos, diagnósticos e terapêuticos. O melhor meio de redu zir a ocorrência de LLcTA seria sustando a transmissão vertical do vírus pela amamentação.

HUMAN T-LYMPHOTROPIC VIRUS 1 (HTLV-1) AND HUMAN T-LYMPHOTROPIC VIRUS 2 (HTLV-2): GEOGRAPHICAL RESEARCH TRENDS AND COLLABORATION NETWORKS (1989-2012)

Publications are often used as a measure of research work success. Human T-lymphotropic virus (HTLV) type 1 and 2 are human retroviruses, which were discovered in the early 1980s, and it is estimated that 15-20 million people are infected worldwide. This article describes a bibliometric review and a coauthorship network analysis of literature on HTLV indexed in PubMed in a 24-year period. A total of 7,564 documents were retrieved, showing a decrease in the number of documents from 1996 to 2007. HTLV manuscripts were published in 1,074 journals. Japan and USA were the countries with the highest contribution in this field (61%) followed by France (8%). Production ranking changed when the number of publications was normalized by population (Dominican Republic and Japan), by gross domestic product (Guinea-Bissau and Gambia), and by gross national income per capita (Brazil and Japan). The present study has shed light on some of the defining features of scientific collaboration performed by HTLV research community, such as the existence of core researchers responsible for articulating the development of research in the area, facilitating wider collaborative relationships and the integration of new authors in the research groups.

Metastatic Pulmonary Calcification in a Patient with Adult T-Cell Leukemia/Lymphoma / 대한내과학회지

Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive disease that is geographically clustered, mirroring areas endemic for human T-cell lymphotropic virus type 1 infection. Most patients with ATLL present with aggressive manifestations such as severe hypercalcemia, lymphadenopathy, hepatosplenomegaly, and bone marrow involvement with progressive thrombocytopenia. We herein report a case of a patient with ATLL exhibiting increased uptake in both lungs as shown on a bone scan using 99mTc-methylene diphosphonate. This finding is thought to have been caused by metastatic calcification associated with ectopic parathyroid hormone production.

A Case of Cytomegalovirus Colitis in Chronic Adult T-Cell Leukemia/Lymphoma / 영남의대학술지

Adult T-cell leukemia/lymphoma (ATLL) is a malignancy of mature T-cells caused by the human T-cell lymphotrophic virus type I (HTLV-I). HTLV-I is endemic in some areas in Japan, the Caribbean basin, and Africa but has low prevalence in South Korea. Patients with ATLL are susceptible to opportunistic infections such as cytomegalovirus (CMV) infection, but CMV infection in chronic ATLL is uncommon. Reported herein is a case involving a 44-year-old woman with chronic ATLL who presented the symptoms of fever and diarrhea. She was suspected to have acute-type ATLL but was later diagnosed with CMV colitis.

Leucemia/Linfoma T Gástrico del adulto: reporte de cuatro casos y revisión de la literatura / Gastric adult T cell Leukemia/Lynphoma: report of four cases and review of literature

Leucemia/Linfoma T del Adulto (ATLL) es una enfermedad agresiva asociada con el virus linfotrópico de células T tipo I (HTLV-1) con presentación y curso clínico heterogéneo. El reporte describe cuatro casos con compromiso gástrico, considerando características clínicas y hallazgos endoscópicos, con la respectiva revisión de la literatura.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive disease associated with human T-cell lymphotropic virus type-I (HTLV-I) with heterogeneous clinical presentation and outcomes. We report four cases with gastric involvement. We describe clinical and endoscopic findings of cases and review literature.

Adult T-cell leukemia/lymphoma: report of two cases / Leucemia/linfoma de células T do adulto: relato de dois casos

Adult T-cell leukemia/lymphoma is a lymphoproliferative disorder of mature T lymphocytes associated with infection with human T-cell lymphotrophic virus type I (HTLV-I). Adult T-cell leukemia/lymphoma is characterized by clinical and laboratory polymorphism that allows it to be classified into four distinct subgroups: smoldering, chronic, acute and lymphomatous types. We present here two cases of adult T-cell leukemia/lymphoma, respectively in the acute and lymphomatous forms of the disease. Case 1 was a 35-year-old woman who presented abdominal distension accompanied by hepatosplenomegaly, adenomegaly, skin lesions, positivity for anti-HTLV-I antibodies and leukocytosis with the presence of flower cells. Case 2 was a 38-year-old man who was admitted with generalized lymphadenomegaly, positivity for anti-HTLV-I antibodies, hypercalcemia and osteolytic lesions. In this paper, we correlate the clinical-laboratory findings of these two cases with data in the literature.

A leucemia/linfoma de células T do adulto é um distúrbio linfoproliferativo de linfócitos T maduros associado à infecção pelo vírus linfotrópico de células T humanas tipo I (HTLV-I). A leucemia/linfoma de células T do adulto tem polimorfismo clínico e laboratorial, que a classifica em quatro subgrupos distintos entre si: smoldering, crônica, aguda e linfomatosa. Apresentamos neste artigo, dois casos de leucemia/linfoma de células T do adulto, respectivamente, nas formas aguda e linfomatosa da doença. O caso 1: uma paciente de 35 anos apresentava distensão abdominal com hepato-esplenomegalia, adenomegalia, lesões cutâneas, anticorpos anti-HTLV-I positivo e leucocitose com presença de flower cell. O caso 2: homem de 38 anos, internado com linfadenomegalia generalizada, anticorpos anti-HTLV-I positivo, hipercalcemia e lesões osteolíticas. Neste artigo correlacionamos os achados clínicos e laboratoriais destes dois casos com dados da literatura.

A Case of Adult T-cell Leukemia/Lymphoma / 대한피부과학회지

Adult T-cell leukemia/lymphoma (ATLL) is a human malignancy associated with human T-cell leukemia virus type I (HTLV-I), which frequently involves the skin. ATLL can be diagnosed based on clinicopathological findings and the presence of anti-HTLV-I serum antibodies and monoclonal integrated HTLV-I provirus in the DNA of tumor cells. It is characterized by leukemia, lymphadenopathy, hypercalcemia, and lytic bone lesions. We report a case of ATLL in a 59-year-old man who developed multiple, scattered papules on the face and trunk. He had a 3-month history of melena. The physical examination showed multiple cervical and axillary lymph node enlargements. On laboratory investigation, the white blood cell count was 113,900/mm(3) with 70% atypical lymphocytes. Histopathological and immunohistochemical analyses of a skin and stomach biopsy confirmed the diagnosis of T-cell lymphoma. Final diagnosis of ATLL was made based on HTLV-I positivity. The patient underwent multiple cycles of combination chemotherapy and combination therapy of zidovudine and interferon-alpha which produced some improvement, but he died of pulmonary complications 3 months after the initial diagnosis.

Complicações pulmonares associadas ao HTLV-I: Relato de 2 casos e revisão da literatura / Pulmonary complications due to HTLV-I. Case Report and Review of literature

Os autores descrevem dois casos de complicações pulmonares pelo vírus linfotrópico de células T human (HTLV-I). Em seguida, apresentam uma breve revisão da literatura discutindo os aspectos mais importantes para o diagnóstico e terapêutica.

The authors describe two cases of pulmonary complications due to human T- lymphotropic virus type I (HTLV-I). Afterall they present a brief review of literature discussing important aspects for the diagnosis and therapeutic.

A Case of Adult T-cell leukemia / lymphoma / 대한피부과학회지

Adult T-cell leukemia/lymphoma (ATLL) is an often aggressive and fatal malignancy of mature CD4+ T lymphocytes, characterized by leukemia, lymphadenopathy, hypercalcemia and lytic bone lesions. Diagnosis of ATLL is based cm abnormal T lymphocytes in the peripheral blood and histologically and cytologically proven lymphoid malignancy with T cell surface antigens. Anti-HTLV-I serum antibodies and demonstration of clonality to HTLV-I proviral DNA are included. We report a case of ATLL in a 64-year-old man who had a painful nodule on the right cheek and multiple scattered papules and nodules on the trunk for 2 months. He had multiple cervical and axillary lymph node enlargements and hepatosplenomegaly. On laboratory finding peripheral leukocytes count was 33,400/mm3 with 63% atypical lymphocytes. Clover-shaped lyrnphocytes with multilobulated nuclei were found in peripheral blood and bone marrow. Histologic findings showed dense bandlike infiltrations of atypical lymphocytes in the dermis with angiocentricity. The surface phenotype of these abnormal cells were CD2+, CD3+, CD4+, CD30+ and HLA-DR+ and HTLV-I specific antibodies were found.

Distinction Between Adult T-cell Leukemia/Lymphoma and Cutaneous Lymphoma / 中华皮肤科杂志

Adult T-cell leukemia/lymphoma (ATLL) and cutaneous T-cell lymphoma (CTCL) have similar clinieopathology and immunophenotype, in order to differentiate the two diseases, 4 eases of ATLL associated cutaneous lesions and 18 eases of CL were studied for elinieopathology, immunophenotype and HTLV-I provirus DNA. Two eases of actinic reticuloid and two eases of lymphocytic infiltration of the skin were selected as negative control. The results showed that four patients of ATLL manifested cutaneous lesions, at same time, they had additional systemic diseases, such as generalized lymphadenopathy, increased levels of LDH and IL-2R, rosette-like cells in their peripheral blood and abnormal bone marrow. The HTLV-I provirus DNA was detected in the peripheral blood, bone marrow, cutaneous lesions and lymph node biopsy specimens of the four patients by PCR amplification of specific HTLV-I DNA fragment. 18 cases of CL were negative for HTLV-I. The study indicates that ATLL may be diagnosed if the patients are associated with CTCL-Iike cutaneous lesions, characteristic histopathological pattern and immunophenotype, rosette-like cells in the peripheral blood and positive HTLV-I provirus DNA.

Adult T-cell leukemia/lymphoma in a Korean: a case report

The clinicopathologic features of a Korean patient with adult T-cell leukemia/lymphoma(ATLL) are presented. A 51-year-old man, who has lived in Korea since birth, had multiple cutaneous nodules and multiple lymphadenopathy for the previous two months. A histopathologic study of the lymph node and skin lesion revealed T-cell non-Hodgkin's lymphoma of pleomorphic type, medium and large cell type. Peripheral blood examination showed leukemic features with 30% of abnormal lymphoid cells. HTLV-I proviral DNA pX region was detected in the DNA from peripheral blood mononuclear cells(PBMC) and the specific gag, pol, and env HTLV-I sequences were detected in the lymph node using polymerase chain reaction technique. Human T-cell leukemia/lymphoma type I(HTLV-I) antibodies were present in the serum. An immunophenotypic study of the lymph node revealed CD4 positive and CD8 negative helper/inducer T cell type surface markers. This case is the acute type, i.e. prototypic ATLL. He was treated with an intensive chemotherapy including cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone. Despite initial transient improvement, the tumor progressed after three cycles of the regimen and became refractory to further chemotherapy. These clinicopathologic findings, including the immunophenotypic analysis, established with certainty the diagnosis of HTLV-I-induced adult T-cell leukemia/lymphoma.