T-Cell Control by Human T-Cell Leukemia/Lymphoma Virus Type 1

Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) causes neoplastic transformation of human T-cells in a small number of infected individuals several years from infection. Collective evidence from in vitro studies indicates that several viral proteins act in concert to increase the responsiveness of T-cells to extracellular stimulation, modulate proapoptotic and antiapoptotic gene signals, enhance T-cell survival, and avoid immune recognition of the infected T-cells. The virus promotes T-cell proliferation by usurping several signaling pathways central to immune T-cell function, such as antigen stimulation and receptor-ligand interaction, suggesting that extracellular signals are important for HTLV-1 oncogenesis. Environmental factors such as chronic antigen stimulation may therefore be of importance, as also suggested by epidemiological data. Thus genetic and environmental factors together with the virus contribute to disease development. This review focuses on current knowledge of the mechanisms regulating HTLV-1 replication and the T-cell pathways that are usurped by viral proteins to induce and maintain clonal proliferation of infected T-cells. The relevance of these laboratory findings is related to clonal T-cell proliferation and adult T-cell leukemia/lymphoma development in vivo.     

Detection of<Emphasis Type="Italic">NOTCH1</Emphasis> Mutations in Adult T-cell Leukemia/Lymphoma and Peripheral T-Cell Lymphoma

We analyzed NOTCH1 gene mutation in 53 adults with mature T-cell leukemia/lymphoma: 21 patients with adult T-cell leukemia (ATL), 25 with T-cell non-Hodgkin's lymphoma (T-NHL), and 7 with T-cell prolymphocytic leukemia. We detected a nonsense mutation, C7249T (resulting in Q2417X, where X is a termination codon) in the PEST domain of NOTCH1 in an ATL patient and detected a 3-bp deletion (positions 7234-7236) that resulted in deletion of a proline codon at codon 2412 in the PEST domain of NOTCH1 in a patient with a T-NHL, peripheral T-cell lymphoma-unspecified (PTCL-u). We also analyzed the expression of NOTCH1 target genes (HES1, CCND1, and MYC), all of which were expressed in the sample of the PTCL-u patient with the NOTCH1 mutation, but found only MYC to be expressed in the sample from the ATL patient. These findings suggest that nonsense mutation in the PEST domain in the ATL case was associated with NOTCH1 signaling through a pathway different from that for T-cell acute lymphoblastic leukemia (T-ALL). Although NOTCH1 mutation occurs infrequently in mature T-cell leukemia/lymphoma, NOTCH1 may be involved in leukemogenesis associated with various forms of T-cell leukemia/lymphoma rather than only with T-ALL.     

Prognosis of Indolent Adult T-Cell Leukemia/Lymphoma

A retrospective chart survey of the clinical features of indolent adult T-cell leukemia/lymphoma (ATL) was conducted in the Miyazaki Prefecture, Japan. This study enrolled 24 smoldering-type ATLs, 10 favorable chronic-type ATLs, and 20 unfavorable chronic-type ATLs diagnosed between 2010 and 2018. Among them, 4, 3, and 10 progressed to acute-type ATLs during their clinical course. The median survival time (MST) in smoldering-type ATL and favorable chronic-type ATL was not reached, and their 4-year overall survival (OS) was 73% and 79%, respectively. Compared with this, the prognosis of unfavorable chronic-type ATL was poor. Its MST was 3.32 years, and the 4-year OS was 46% (p = 0.0095). In addition to the three features that determine the unfavorable characteristics of chronic-type ATL, namely, increased lactate dehydrogenase, increased blood urea nitrogen, and decreased albumin, the high-risk category by the indolent ATL-Prognostic Index, which was defined by an increment of soluble interleukin-2 receptor (sIL2-R) of >6000 U/mL, could explain the poor prognosis in indolent ATL patients. The level of sIL-2R might be an indicator of the initiation of therapy for indolent ATL.     

Two Cases of Secondary Acute Myeloid Leukemia Accompanying Adult T-Cell Leukemia/Lymphoma

We identified 2 cases of secondary acute myeloid leukemia (AML) following adult T-cell leukemia/lymphoma (ATL) in patients who had previously received chemotherapy. Both cases were thought to represent therapy-related AML because the patients had previously received combination chemotherapy including epipodophyllotoxin, anthracycline, and alkylating agents for the ATL. The cases were diagnosed as AML M4 with eosinophilia and AML M2, with the chromosomal abnormalities inv(16)(p13q22) and t(8;21)(q22;q22), respectively. In our hospital, only these 2 cases of secondary AML accompanying ATL were identified among 90 cases of acute- or lymphoma-type ATL diagnosed from October 1999 to July 2006. The frequency of coexisting AML and ATL is lower than that reported for acute leukemia coexisting with other lymphoid malignancies. The low frequency of secondary leukemia with ATL may be associated with the short survival times of ATL patients.     

Nationwide Hospital-Based Survey of Adult T-Cell Leukemia/Lymphoma in Japan

Nationwide surveys of adult T-cell leukemia/lymphoma (ATL) have played an important role in helping us to understand the pathophysiology of this disease and analyze its prognosis in Japan. Classifications of clinical subtypes have been proposed based on the results of nationwide surveys of patients with ATL diagnosed in the 1980s. This article highlighted the classification and prognosis of ATL based on different surveys and focused on the comparison of data derived from the available surveys. The 11th nationwide hospital-based survey was conducted in patients with ATL diagnosed in 2010–2011 using the same method as that used in the 1980s survey. The median age of disease onset was 68 years, which was increased compared with previous surveys. While median survival of patients with the acute and lymphoma types had not improved much since the 1980s, the 4-year survival rate was higher. Little improvement in the prognosis was observed for the chronic and smoldering types. The 12th nationwide survey of patients with ATL diagnosed in 2012–2013 also showed an increase in age at onset. Further epidemiological research that includes more cases is needed to deepen our understanding of the actual state of treatment and prognosis of this disease.     

Immunologic Control of Human T-Cell Leukemia Virus Type I and Adult T-Cell Leukemia

Host T-cell responses to human T-cell leukemia virus type I (HTLV-I) control the expansion of HTLV-I-infected cells and are determinants of the equilibrium proviral load in vivo. Insufficient T-cell responses are regarded as an immunologic risk factor for adult T-cell leukemia (ATL) because they allow increased proviral loads, which represent an epidemiologic risk factor for ATL. ATL cells from approximately half of ATL cases retain the ability to express HTLV-I Tax, a major target antigen of HTLV-I-specific cytotoxic T-lymphocytes (CTL), whereas Tax-specific CTL in ATL patients are inactive. Tax-specific CTL responses are strongly activated after hematopoietic stem cell transplantation in some ATL patients in long-term remission, indicating that HTLV-I Tax is expressed in vivo rather than being silent, and that the donor-derived T-cell system can recognize it. These findings strongly suggest that reactivation of Tax-specific CTL by vaccines may be promising for prophylaxis of ATL in the high-risk group of HTLV-I carriers and for therapy of ATL in patients whose tumor cells are capable of expressing Tax.     

CD20- and CD56-Positive T-Cell Large Granular Lymphocyte Leukemia in a Human T-Cell Leukemia Virus Type 1 Carrier

A 60-year-old man was diagnosed with asymptomatic T-cell granular lymphocyte (T-LGL) leukemia in September 2006. He was serologically positive for human T-cell leukemia virus type 1 (HTLV-1). However, monoclonal integration of the HTLV-1 genome was not detected in the peripheral blood, suggesting that HTLV-1 did not contribute to the pathogenesis of T-LGL leukemia in the present case. Phenotypically, neoplastic cells of our case were CD3+, CD4*, CD8+, CD16-, CD56+, CD57*, and T-cell receptor (TCR) alphabeta+. They also coexpressed CD20 antigen with weak intensity. This represented a unique case of T-LGL leukemia showing a typical clinical and phenotypic features.     

Leukemogenesis of Adult T-Cell Leukemia

Adult T-cell leukemia (ATL) is one of the most aggressive hematologic malignancies and is caused by human T-cell leukemia virus type I (HTLV-I). Tax, encoded by the HTLV-I pX region, has been recognized by its pleiotropic actions as a critical accessory protein playing a central role in leukemogenesis. However, fresh ATL cells frequently lose Tax protein expression via several mechanisms, such as genetic and epigenetic changes in the provirus. Furthermore, there is a long latency period before the onset of ATL, indicating the multistep mechanisms of leukemogenesis. Therefore, additional factors, including other viral proteins, genetic and epigenetic changes of the host genome, and alterations in the gene expression and immune systems of the host cells, may be implicated in ATL leukemogenesis. This review summarizes recent advances in the understanding of ATL leukemogenesis.     

Case of a Patient with Progressive Adult T-Cell Leukemia/Lymphoma Treated Successfully by Reduced-Intensity Conditioning Stem Cell Transplantation from an HLA-Incompatible Related Donor

A 61-year-old man with progressive adult T-cell leukemia/lymphoma (ATLL) successfully received reduced-intensity conditioning stem cell transplantation (RIST) without T-cell depletion (TCD) from his HLA-incompatible son, who had negative results for human T-lymphotropic virus type 1 (HTLV-1) (1-locus, 1-allele mismatch in the graft-versus-host [GVH] direction; 2-loci, 1-allele mismatch in the host-versus-graft direction). The preparatory regimen consisted of fludarabine, busulfan, and rabbit antithymocyte globulin. GVH disease (GVHD) prophylaxis consisted of short-term administration of methotrexate, tacrolimus, and methylprednisolone. The patient achieved complete donor chimerism on day 30 after transplantation. On approximately day 50 the patient started to experience steroid-refractory skin GVHD (grade IV), which was successfully managed with basiliximab (anti-CD25 monoclonal antibody) and mycophenolate mofetil (MMF). Serial analysis of HTLV-1 proviral load by quantitative polymerase chain reaction analysis using whole peripheral blood demonstrated undetectable levels from day 90. At the time of this writing the patient had been in complete remission for more than 16 months. The results in this case suggest the potential of non-TCD RIST from an HLA-incompatible relative donor as an alternative source of hematopoietic stem cells even for an elderly patient with advanced ATLL. In addition, basiliximab combined with MMF may be effective for the treatment of steroid-refractory skin GVHD without deteriorating the graft-versus-ATL effect.     

Human T-Cell Leukemia Virus Type 1 Tax and Cellular Transformation

Infection of T-cells by human T-cell leukemia virus type 1 (HTLV-1) causes a lymphoproliferative malignancy known as adult T-cell leukemia (ATL). ATL is characterized by abnormal lymphocytes, called flower cells, which have cleaved and convoluted nuclei. Tax, encoded by the HTLV-1 pX region, is a critical nonstructural protein that plays a central role in leukemogenesis; however, the mechanisms of HTLV-1 oncogenesis have not been clarified fully. In this review, we summarize current thinking on how Tax may affect ATL leukemogenesis.     

Current Status of Therapeutic Approaches to Adult T-Cell Leukemia

More than 2 decades have elapsed since the proposal of adult T-cell leukemia (ATL). Since then, the discovery of the etiologic virus, human T-cell leukemia virus type I (HTLV-I), and the establishment of the diagnostic steps of serum test and molecular study have clearly defined ATL as a distinct disease entity. Because conventional chemotherapy, which is active against other lymphoid malignancies, was proven to be ineffective for treating aggressive forms of ATL, ATL has become the target of several clinical studies for the purpose of improving therapeutic outcomes. Combination chemotherapy exclusively designed for ATL has considerably elevated the treatment response rate in ATL patients, but it has not sufficiently extended the median survival time. The introduction of antiviral agents has led to surprising effects for patients with acute ATL. Monoclonal antibodies seem to be promising, especially for patients with chemotherapy-resistant disease. Unfortunately, these approaches did not prove to be sufficient for most patients with ATL to obtain long-term survival. Recent promising reports on allogeneic stem cell transplantation (allo-SCT) for ATL have suggested that allo-SCT could overcome the limitations that other treatment modalities have not surmounted. More efforts are clearly needed to clarify the usefulness of allo-SCT, especially with reduced-intensity conditioning regimens, for ATL patients.     

A Rare Case of Adult T Cell Leukemia/Lymphoma: Clinicopathological Correlation with Autopsy Confirmation

Adult T cell leukaemia/lymphoma (ATLL) is a rare T lymphoproliferative disorder which is etiologically linked with human T cell lymphotropic virus type-1 (HTLV-1). HTLV-1 is endemic in Japan, Caribbean and Africa. The highest incidence of ATLL is in Japan although sporadic cases have been reported elsewhere in the world. We describe a case of ATLL with an unusual presentation with clinic-pathological correlation and autopsy confirmation. A 56 year old male was referred to Command Hospital (Southern Command) for an incidental finding of lymphocytosis on a routine Hemogram. Clinical examination did not reveal hepatosplenomegaly, lymphadenopathy, jaundice or skin lesions. Laboratory investigations showed lymphocytosis with predominance of atypical lymphomonocytoid cells. Immunophenotyping of the bone marrow mononuclear cells showed positivity for CD45, CD2, CD3, CD4, CD5 and negative for CD7, CD8, CD13, CD33, CD19, which is characteristic of ATLL phenotype. Clonality was confirmed by PCR for TCR gene rearrangement on post mortem tissue. He succumbed to his illness after 40 days of initial presentation and 16 days of being diagnosed as ATLL. Here, we discuss the pathogenesis and characteristics of ATLL with clinico-pathological correlation and autopsy confirmation.     

Recent Advances in Therapeutic Approaches for Adult T-cell Leukemia/Lymphoma

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell lymphoma caused by human T-cell leukemia/lymphoma virus type 1 (HTLV-1). ATLL occurs in approximately 3%–5% of HTLV-1 carriers during their lifetime and follows a heterogeneous clinical course. The Shimoyama classification has been frequently used for treatment decisions in ATLL patients, and antiviral therapy has been reportedly promising, particularly in patients with indolent type ATLL; however, the prognosis continues to be dismal for patients with aggressive-type ATLL. Recent efforts to improve treatment outcomes have been focused on the development of prognostic stratification and improved dosage, timing, and combination of therapeutic modalities, such as antiviral therapy, chemotherapy, allogeneic hematopoietic stem cell transplantation, and molecular targeted therapy.     

Clinical Significance of Tumor-associated Antigen RCAS1 Expression in Human Pancreatic Ductal Adenocarcinoma

Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is a human tumor-associated antigen that induces cell cycle arrest and/or apoptosis in RCAS1 receptor-expressing immune cells. The aim of the present study was to evaluate the clinical significance of RCAS1 expression in human pancreatic adenocarcinoma. Immunohistochemical analysis of RCAS1 expression was performed on paraffin-embedded tissue sections obtained from 76 pancreatic adenocarcinoma patients. RCAS1 positivity and overexpression and intensity of the staining were correlated with clinicopathological parameters, proliferative capacity and patient survival. Of the 76 adenocarcinoma patients, 65 (86%) tested positive for RCAS1; of these 65 RCAS1-positive cases, 36 (55%) showed RCAS1 overexpression. RCAS1 positivity was statistically significantly correlated with the histopathological grade of the tumor (P = 0.026), and it showed a trend to be correlated with tumor size (P = 0.071). RCAS1 intensity and overexpression of staining showed a trend to be correlated with the histopathological grade of the tumor (P = 0.061 and P = 0.089, respectively), whereas RCAS1 positivity and the overexpression and intensity of staining were not statistically significantly correlated with the proliferative capacity of the tumor or any other clinicopathological parameter examined nor with patients’ survival. Our data provide evidence for the implication of RCAS1 in pancreatic neoplasia. However, the prediction of survival using RCAS1 expression as a marker seems uncertain for this type of cancer.     

Expression of apoptosis-associated protein RCAS1 in macrophages of histiocytic necrotizing lymphadenitis

Receptor-binding cancer antigen expressed on SiSo cells (RCAS1), which is recognized by the 22-1-1 monoclonal antibody (MoAb) against human uterine adenocarcinoma cell line SiSo, has been identified on various kinds of cancer cells. RCAS1 appears to be an apoptosis-associated protein that induces apoptosis in activated T-cells and erythroid progenitor cells. We previously demonstrated that monocytes/macrophages express RCAS1. In the present study, we investigated RCAS1 expression by 22-1-1 MoAb in histiocytic necrotizing lymphadenitis (HNL), which is characterized by necrotic lesions consisting of T-cells undergoing apoptosis and macrophages in proliferation. Expression of RCAS1 was analyzed by immunohistochemical staining in 9 cases of HNL and in 9 cases of reactive lymphadenitis used as a control. The ratio of RCAS1+ cells to CD68+ cells (monocytes/macrophages) was significantly higher in the patients with HNL than in the patients with reactive lymphadenitis (P = .0002; paired t test). Our findings suggest that RCAS1 expressed on macrophages may play an important role in the induction of activated T-cell apoptosis in cases of HNL.     

Adult T Cell Leukemia/Lymphoma Becoming Apparent during Treatment of Pulmonary Abscess and Empyema Caused by Nocardia asiatica: A Case Report and Review of the Literature

Nocardia is a Gram-positive bacterium that causes opportunistic infections. Nocardia asiatica was newly isolated in 2004, and there have been no case reports describing the empyema caused by N. asiatica. Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). We herein report a case in which immunosuppression attributable to ATL may have led to pulmonary abscess and empyema caused by N. asiatica. Our case demonstrates the need to investigate causes of immunosuppression, including ATL, in patients showing nocardiosis.