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.     

Expression of Human Tumor-Associated Antigen RCAS1 in Adult T-Cell Leukemia/Lymphoma

In human cancer, RCAS1 (the receptor-binding cancer antigen expressed on SiSo cells) on the surface of various kinds of tumor cells reportedly induces the apoptosis of T-cells and natural killer cells, resulting in evasion of the immune system. In the present study, an immunohistochemical analysis of RCAS1 expression was performed with lymph node specimens obtained from patients with adult T-cell leukemia/lymphoma (ATLL). Positive staining was seen in 15 (75%) of 20 cases and in all cases of patients with short survival times. In the cases of B-cell lymphomas, positive staining was seen in only 1 (13%) of 8 cases. These findings indicate that expression of RCAS1 may be associated with the evasion from immune surveillance of cells infected with human T-lymphotropic virus type I, resulting in the development of overt leukemia/lymphoma. Determination of RCAS1 expression may be useful for predicting the prognosis of patients with ATLL.     

Implication of the <Emphasis Type="Italic">HTLV- I bZIP Factor</Emphasis> Gene in the Leukemogenesis of Adult T-Cell Leukemia

Adult T-cell leukemia (ATL) is a leukemia derived from CD4+ mature T-cells and induced by human T-cell leukemia virus type I (HTLV-I) infection. Although previous studies have revealed many aspects of its leukemogenesis, enigmas remain about how HTLV-I transforms mature T-cells in infected individuals. Furthermore, an effective therapy for ATL has not yet been established. The critical role of a nonstructural regulatory viral protein, Tax, in transformation has been established through many molecular studies, in vitro cell culture experiments, and transgenic mouse model systems. In addition, other accessory viral proteins have been implicated in ATL pathogenesis. Recent studies of a minus strand viral gene, HTLV-I bZIP factor (HBZ), suggest it plays a role in ATL leukemogenesis. In addition to viral components, genetic and epigenetic events of the host cellular genome must be considered in developing a complete picture of the transformation process. In this review, we summarize the molecular and cellular mechanisms involved in the leukemogenesis induced by HTLV-I; we consider both viral and host cellular factors and focus particularly on the viral gene HBZ.     

<Emphasis Type="Italic">hSNF5</Emphasis><Emphasis Type="Italic">/INI1</Emphasis> mutation analysis in acute myeloid leukemia

Previous studies indicated that region 11.2 of the long arm of chromosome 22 (22q11.2) might be a locus encoding a tumor suppressor gene, since its deletion is a recurrent genetic characteristic of aggressive pediatric cancer. This region is found in the human immunodeficiency virus integrase interactor 1 (hSNF5/INI1) gene. To investigate whether the hSNF5/INI1 gene is involved in leukemogenesis, mutation analysis of the hSNF5/INI1 gene was performed in the present study using 5 hematopoietic cell lines, acute myeloid leukemia (AML) specimen and normal control. We found two single nucleotide polymorphisms at the hSNF5/INI1 gene in exon 4 and exon 9. The results of this study suggest that the hSNF5/INI1 gene does not play an important role in the leukemogenesis of AML.     

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.     

Establishment of thymoma-prone congenic rat strain,ACI.BUF/Mna-<Emphasis Type="Italic">Tsr1</Emphasis>/<Emphasis Type="Italic">Tsr1</Emphasis>

Purpose To confirm the presence of the susceptible gene for the thymoma development in the region that was assumed by the previous linkage study by Oyabu et al. (J Natl Cancer Inst 91:279–282, 1999), we tried to establish a congenic strain of rats. Methods Backcrossings between the BUF/Mna strain as a donor strain and the ACI/NMna strain as an inbred partner were repeated for 12 generations, examining whether rats had the thymoma development region, and then homozygous rats were yielded by mating among the heterozygotes. To detect the phenotypic expression, heterozygous ACI.BUF/Mna-Tsr1/+ (ACI-Tsr1/+) rats were generated by crossing female ACI.BUF/Mna-Tsr1/Tsr1 (ACI-Tsr1/Tsr1) rats with male ACI/NMna rats and were maintained for 24 months. Results These ACI-Tsr1/+ rats produced thymoma in 71%, showing a dominant trait. The thymomas were of the lymphocyte predominant type, as those developed in rats of the original BUF/Mna strain. Conclusions Thus, a new rat congenic strain, ACI-Tsr1/Tsr1, was established, revealing that thymoma develops in the dominant trait in ACI-Tsr1/+ rats.     

Coexistent Rearrangements of c-<Emphasis Type="Italic">MYC</Emphasis>,<Emphasis Type="Italic">BCL2</Emphasis>, and<Emphasis Type="Italic">BCL6</Emphasis> Genes in a Diffuse Large B-Cell Lymphoma

We present a patient with stage III de novo diffuse large B-cell lymphoma. The lymphoma cells showed mature B-cell immunophenotype but lacked surface immunoglobulin (Ig) expression. Long-distance and long-distance inverse polymerase chain reaction assays to detect the oncogene/Ig gene rearrangement revealed that the cells carried 3 independent fusion genes, namely, c-MYC/Ig heavy chain gene (IgH), BCL2/IgH, and Ig lambda light chain gene/BCL6. Thus, the lymphoma cells concurrently carried t(8;14)(q24;q32), t(14;18)(q32;q21), and t(3;22)(q27;q11), which developed in association with class switching, V/D/J recombination, and somatic hypermutation, respectively. The lymphoma responded to chemoradiotherapy, and the patient has been well for 2 years, suggesting that multiple oncogene rearrangements may not necessarily be associated with poor clinical outcome.     

<Emphasis Type="Italic">GSTP1</Emphasis> and <Emphasis Type="Italic">MDR1</Emphasis> Genotypes and Central Nervous System Relapse in Childhood Acute Lymphoblastic Leukemia

The probability of event-free survival of childhood acute lymphoblastic leukemia (ALL) approaches 80% or more with the use of modern multiagent chemotherapeutic regimens. One major contribution to this success has been reduction of the rate of central nervous system (CNS) relapses to less than 5%. However, heterogeneity is observed with regard to the incidence of CNS relapse in homogenously treated patient populations. One potential explanation for this heterogeneity is variation in the genetic background of these populations. Glutathione S-transferase P1 and P-glycoprotein are implicated in resistance to a variety of chemotherapeutic agents and have been localized to the blood-brain barrier. In a matched case-control study, we investigated the associations between CNS relapse in childhood ALL and the presence of phenotypically relevant single nucleotide polymorphisms within the GSTP1 (codon 105 and 114) and MDR1 genes (ABCB1; coding for Pgp; exon 26, C3435T). Significant reductions in risk of CNS relapse were observed for patients homozygous for the GSTP1 Val105 allele as well as for patients with the MDR1 3435T/T or C/T genotype. For both genotypes, the effect was restricted to patients at intermediate or high risk of treatment failure. These results suggested a modulating role for host genetic variation in the development of CNS relapse in childhood ALL treated according to Berlin-Frankfurt-Münster protocols.     

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.     

Case of B-Cell Lymphoma with Rearrangement of the <Emphasis Type="Italic">BCL1, BCL2, BCL6</Emphasis>, and <Emphasis Type="Italic">c-MYC</Emphasis> Genes

We managed a peculiar case of lymphoma showing immunohistochemical overexpression of cyclin D1. At initial examination the patient had meningeal lymphomatosis and general lymphadenopathy. Histologic examination of biopsy specimens of inguinal lymph nodes showed tumor cells and vague nodular growth resembling lymphoblasts. The results of flow cytometric analysis were positive for CD10, CD20, CD103, and immunoglobulin G (IgG) and Ig kappa and were negative for CD5, CD23, and terminal deoxynucleotidyl transferase activity. Results of immunohistochemical analysis of paraffin-embedded specimens were positive for cyclin D1 and Bcl2 in the tumor cells. Sixty percent of tumor cells had positive results for MIB1/Ki67. Cytogenetic and molecular studies revealed tumor cells simultaneously had t(14;18)(q32;q21), t(11;22)(q13;q11), t(8;14)(q24;q32), and t(3;14)(q27;q32) with the rearrangement of BCL1, BCL2, BCL6, and c-MYC genes. Lymphadenopathy showed a quick and complete response to doxorubicin-containing systemic chemotherapy with rituximab, but the central nervous system disease progressed and killed the patient.     

Successful All-<Emphasis Type="Italic">trans</Emphasis> Retinoic Acid Treatment of Acute Promyelocytic Leukemia in a Patient with <Emphasis Type="Italic">NPM/RAR</Emphasis> Fusion

Acute promyelocytic leukemia (APL) is characterized by a reciprocal chromosomal translocation involving the gene for retinoic acid receptor alpha(RAR). Most APL patients have a t(15;17) translocation that generates the PML-RAR fusion gene, and such patients respond well to treatment with all-trans retinoic acid (ATRA). Some APL cases also involve rearrangements that fuse RAR to partner genes other than PML, including nucleophosmin (NPM), promyelocytic leukemia zinc finger (PLZF), nuclear mitotic apparatus (NUMA), and Stat5b, but the clinical characteristics of APL without PML-RAR have not been fully clarified. We describe a 64-year-old man with NPM-RAR-positive APL who was receiving hemodialysis therapy for chronic uremia. Complete remission was achieved with ATRA monotherapy and was maintained for 18 months with consolidation chemotherapy. These findings suggest that ATRA can be used to treat APL patients with NPM/RAR as well as APL with PML/RAR.