The Differences between Lymphoma and Leukemia Type of Adult T-cell Leukemia

The difference between lymphoma type and leukemia type of adult T-cell leukemia (ATL) were analysed with 102 Japanese patients all positive for human T-cell leukemia virus type I (HTLV-I) antibody. They were classified into three groups on findings at first medical examination: lymphoma type cases, leukemia type cases, and mixed type (leukemia type plus lymphadeno-pathy) cases. Lymphoma type patients had several or more enlarged lymph nodes the largest of which was greater than 1 cm in diameter and with practically no abnormal lymphocytes (ATL. cells), which are characteristic of ATL, in the peripheral blood. Leukemia type patients had 10% or more ATL cells in the peripheral blood and had no detectablle lymphadenopathy Lymphoma type patients often complained of detectable lymphadenopathy, while leukemia type patients complained frequently of general fatigue and skin eruption. Mixed type patients more frequently had signs and symptoms which were characteristic of both types: lymphadenopathy and 10% or more ATL cells in the peripheral blood. Mixed type: ATL had a poorer prognosis than either lymphoma type or leukemia type. The median survival time was 3 months for mixed type patients, 10.5 months for lymphoma type patients, and 13.5 months for leukemia type patients. Complications and causes of death have also been touched upon. Clinicians are thus advised to consider ATL patients separately according to their clinical manifestations.     

Concurrence of lymphoma type adult T-cell leukemia in three sisters

Three sisters, ranging in age from 56 to 59 years, who developed lymphoma type adult T-cell leukemia (ATL) during a 19-month period are described. The patients were born in the Amakusa area of Kumamoto Prefecture, an area where the incidence of malignant lymphoma is high. The histologic diagnosis, made on the basis of the Lymphoma Study Group in Japan (LSG) classification of lymph nodes, was diffuse, medium-sized cell type in the elder sister, and mixed cell type in the middle and younger sisters. The patients and their elder brother had serum antibodies against ATL-associated antigens (ATLA).     

Human T-cell leukaemia virus in Africa: possible roles in health and disease

Observation of clustering of adult T-cell leukaemia/lymphoma (ATL) in the coastal areas of southern Japan led to speculations about its association with an environmental agent. Human T-cell lymphoma/leukaemia virus (HTLV) was later identified as the probable causal agent in these and similar cases of lymphoma/leukaemia, which were subsequently observed in first-generation West Indian Black emigrants living in England and the USA, in the forest areas of South America and in some south-eastern states of the USA. HTLV antibodies have also been identified in cases of malignant lymphoproliferative diseases (MLPD) in Ibadan and Zaria in Nigeria and in the sera of cancer patients from various parts of Africa, thus indicating that Africa is a major region for HTLV infection. Evidence is presented of the association of HTLV infection in Africa not only with T-cell but also B-cell neoplasia, such as Burkitt's lymphoma and chronic lymphocytic leukaemia (CLL). The prevalence rates of infection in normal blood donors appear to range from 3.7% in sub-Sahelian northern Nigeria to 10-15% in the south-western rain-forest area of Nigeria.     

Antibodies against three purified structural proteins of the human type-C retrovirus,HTLV, in Japanese adult T-cell leukemia patients,healthy family members,and unrelated normals

The immunological relationship of human T-cell leukemia/lymphoma virus (HTLV) and the virus found in Japanese adult T-cell leukemia/lymphoma (ATL) was investigated in detail by testing the specific binding of serum antibodies from Japanese ATL patients and normal Japanese donors to the purified HTLV proteins p24, p19, and p15. Sera were prescreened for antibodies to p24. Of those positive, 67% of the ATL sera and 78% of the normal sera were further shown to have antibodies against p19. In both groups 17% had antibodies to p15. Generally, the average antibody titers were twice as high in ATL as in normal sera. Competition radioimmunoprecipitation assays done with various sera and involving HTLV-producing cells, virus-positive cells from a Japanese ATL patient, and virus-positive cultured T cells of one of his healthy family members as competing materials demonstrated no differences between the p24, p19, and p15 found in these cells. These results provide strong and detailed immunological evidence that the human retrovirus isolates first made from US patients with cutaneous T-cell malignancies, and those made later in Japanese ATL are either identical or very closely related strains of the same virus, HTLV, a finding verified in other detailed analyses of the HTLV genomes of the respective isolates. To date only HTLV-II, isolated from a US case of hairy-cell leukemia of a T-cell type, is a distinct additional human retrovirus class.     

Transformation of hamster spleen lymphocytes by human T-cell leukemia virus type I

Co-cultivation of spleen cells of Syrian golden hamsters with lethally irradiated MT-2 cells harboring human T-cell leukemia virus type I (HTLV-I) resulted in the establishment of lymphoid cell lines, HCT-1 and HCT-2, which exhibited the normal karyotype of golden hamsters. Cells of both the HCT-1 and HCT-2 lines lacked surface immunoglobulins and reacted with a monoclonal antibody (MAb) specific for hamster T cells. Some were positive for OKIa1. None of them expressed HTLV structural antigens (p19 and p24) or virus particles, but they contained HTLV-I proviral DNA monoclonally. By immunochemical analysis of the labelled cell antigens, sera from adult T-cell leukemia (ATL) patients reacted with the two polypeptides, p37 and p40, which may not be viral structural proteins and still remain to be characterized. HCT-1 and HCT-2 cells were transplantable into newborn hamsters, pre-treated with anti-hamster thymocyte serum and non-treated, respectively, producing diffuse malignant lymphoma. These findings indicated that HTLV-I not only immortalized but also transformed hamster T cells non-productively.     

Effect of tumor promoters on human T cell leukemia/lymphoma virus (HTLV)-structural protein induction in adult T-cell leukemia cells

We assayed the capacity of tumor promoters to induce human T-cell leukemia/lymphoma virus (HTLV) structural proteins p19 and p24 from the HTLV genome-carrying adult T-cell leukemia (ATL) cell lines, MT-1 and KH-2Lo, and fresh ATL cells. Among the tested substances, 12-O-tetradecanoyl phorbol-13-acetate (TPA), 12-hexadecanoyl-phorbol-13-acetate (HPA) and teleocidin induced HTLV structural protein p19 and p24. This suggests that certain environmental substances, especially those known to be tumor promoters, may activate the HTLV-gene in ATL cells.     

Adult T-cell leukemia in two siblings. Acute crisis of smoldering disease in one patient

Two cases of human T-cell leukemia virus (HTLV)-positive adult T-cell leukemia (ATL) in brother and sister are presented. Six of 15 members of this family were seropositive for antibodies for ATL-associated antigens (ATLA). The sister of the ATL patient developed overt ATL after 5 years and 8 months of smoldering ATL. Immunologic examinations during the smoldering phase were normal except for negative skin tests for purified protein derivative. Factors leading to the induction of ATL among HTLV carriers remain to be studied.     

Differences in prognostic factors between leukemia and lymphoma type of adult T-cell leukemia

Prognostic factors affecting the survival of adult T-cell leukemia (ATL) patients were analyzed in three groups: total cases, leukemia type cases, and lymphoma type cases. Factors found to be important overall, i.e. for total cases, were leukocyte count, ATL cell ratio in the peripheral blood, serum calcium levels and lactate dehydrogenase (LDH) level. Of those, LDH level proved not significant when evaluated separately for leukemia type or lymphoma type cases. Leukocyte count and ATL cell ratio were significant in leukemia type patients, whereas it was serum calcium level that was significant in lymphoma type; there were mutually exclusive sets of factors for the two groups. Thus, prognostic factors for ATL patients should be considered separately for each type of the disease.     

Methylenetetrahydrofolate reductase genotype does not play a role in adult T-cell leukemia/lymphoma pathogenesis among human T-lymphotrophic virus type 1 carriers

Human T-lymphotropic virus type 1 (HTLV-1) is associated with adult T-cell leukemia/lymphoma (ATL). However, the incidence of ATL is low among HTLV-1 carriers suggesting additional mechanisms are involved in the progression of the disease. A recent study found that polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene influence the susceptibility to malignant lymphoma. We have analyzed the MTHFR genotype in 81 HTLV-1 carriers and 87 ATL patients. No statistically significant associations were found between MTHFR genotype and development of ATL. These data suggest that genetic polymorphisms in the MTHFR locus do not play a role in ATL pathogenesis among HTLV-1 carriers.     

Cell surface phenotypes and expression of viral antigens of various human cell lines carrying human T-cell leukemia virus

Human T-cell leukemia/lymphoma virus (HTLV)-carrying cells from various origins were characterized by cell surface markers and expression of HTLV antigens. Eight cell lines named TCL were obtained by transformation of peripheral blood leukocytes (PBL) of healthy donors or HTLV carriers in cocultures with HTLV-producer MT-2 cells. Nine cell lines named ILT were interleukin 2 (IL2)-dependent cell lines cloned from PBL of ATL patients and healthy HTLV-carriers. Tc-Kan9 cell line was also an IL2-dependent cell line clonally established from PBL culture stimulated with autologous TCLcells. Five cell lines named TL were established in vitro directly from PBL of an adult T-cell leukemia (ATL) patient and from ILT cells of an ATL patient and three HTLV-carriers, respectively, to grow autonomously without IL2. All the TCLs, ILTs, TLs and Tc-Kan9 possessed Leu-I antigen, a pan-T-cell marker. Leu3a antigen, a helper/inducer T-cell marker, was expressed on five of eight TCLs and all of the ILTs and TLs. Leu-2a, a cytotoxic/suppressor T-cell marker, was detected only on Tc-Kan9 but not others. Fresh ATL leukemic cells of patients had a helper/inducer T-cell marker. Ia, OKT9 and Tac antigens, markers for activated and differentiated T cells, were strongly expressed on all of the cell lines tested and fresh ATL leukemic cells were weakly positive for these antigens. Expression of HTLV antigens detected by mouse monoclonal antibodies and an ATL-patient serum varied among these cell lines. One TL, two ILTs and most of the fresh ATL leukemic cells did not express HTLV antigens on the cell surface. The other cell lines were all positive for the surface viral antigens. However, molecular species of antigens defined by radioimmunoprecipitation with an ATL-patient serum were not always identical among the cell lines. Molecular weights of polypeptides detectable in most of the cell lines were 62K, 46K, 40K, 24K, 21K and 19K which could never be detected in several control T-cell lines. 68K and 28K polypeptides were frequently detected in MT-2 and TCLs. GINI4, a mouse monoclonal antibody against HTLV core protein (p19) detected not only p19 in various cell lines but also p28, p29, p31 or p40 in certain cell lines tested. B-cell lines named LCL were established and cloned from PBL of two HTLV-carriers by EB-virus-induced transformation and they also expressed HTLV antigens, la, OKT9 and Tac antigens. Expression of Tac and HTLV antigens of fresh ATL leukemic cells were induced or enhanced after in vitro short-term cell cultivation with crude IL2.     

Jejunal perforation in a patient with adult T-cell leukemia

We present a case of adult T-cell leukemia (ATL) with jejunal perforation at the site of intestinal involvement by ATL. A 39-year-old woman presented with sudden-onset abdominal pain. Physical examination showed generalized severe abdominal tenderness and intraabdominal free air was seen on radiographic examination. Under a diagnosis of peritonitis due to intestinal perforation, an emergency operation was performed. A pinhole-like perforation was found in the jejunum 80 cm distal to Treitz's ligament, and the patient underwent partial resection of the affected jejunum. Microscopic examination revealed diffuse infiltration of abnormal lymphocytes into the entire wall of the jejunum and mesenteric lymph nodes. A diagnosis of ATL was confirmed by the presence of antibody to human T-lymphotropic virus type 1 (HTLV-1) in the serum, a positive result for T-cell markers and the HTLV-1 proviral genome in the mononuclear cells in the specimens. The final diagnosis was thus lymphoma subtype of ATL. Combination chemotherapy was repeated until the patient died 14 months postoperatively. Emergent surgery followed by intense chemotherapy might improve survival in patients with ATL and perforated intestine.     

Acute T-cell leukemia/lymphoma mimicking Hodgkin's disease with secondary HTLV I seroconversion

The authors observed a pleiomorphic lymphoma mimicking Hodgkin's lymphoma in a French Guyana black woman lacking antibodies for human T-cell lymphoma/leukemia virus type I (HTLV I). After two courses of chemotherapy with either mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) or doxorubicin, bleomycin, vincaleukoblastine, and dacarbazine (ABVD), a typical acute T-cell leukemia/lymphoma developed with HTLV I seroconversion. Specific HTLV I DNA sequences were detected using the polymerase chain reaction (PCR) on a lymph node biopsy obtained before chemotherapy. The mechanisms of the seroconversion are discussed.     

Cytotoxicity of interleukin 2-toxin toward lymphocytes from patients with adult T-cell leukemia

The inhibitory effect of a diphtheria toxin-related interleukin 2 fusion protein, IL-2-toxin, on protein synthesis in adult T-cell leukemia/lymphoma (ATL) cells was examined in vitro. Peripheral blood ATL cells from 12 patients (six acute type, four chronic type, and two smoldering type ATL) and the lymph node cells from three ATL patients (two acute type and one lymphoma type ATL) were examined. At a concentration of 10(-8) M, IL-2-toxin inhibited protein synthesis by 60 to 98% in lymph node ATL cells, whereas protein synthesis in peripheral blood ATL cells was inhibited from 20 to 57% in acute type, and from 3 to 13% in chronic type. In contrast, IL-2-toxin had no measurable effect on T-cells from either patients with smoldering type ATL or normal controls. The cytopathic effects of IL-2-toxin were blocked by the addition of anti-CD25 monoclonal antibody, suggesting that the inhibition of protein synthesis in target cells was mediated by the IL-2 receptor (IL-2R). The degree of inhibition of protein synthesis, however, was not closely correlated with expression of CD25 antigen (low-affinity Mr 55,000 glycoprotein, IL-2R, Tac antigen) on ATL cells. There was an apparent correlation between the degree of inhibition and the rate of protein synthesis in ATL cells. We demonstrate that ATL cells from patients with acute or lymphoma type disease were more sensitive to IL-2-toxin than cells from chronic or smoldering disease. These findings suggest that the high affinity IL-2R present on acute and lymphoma type ATL cells may serve as a target for therapy with this recombinant chimeric toxin.     

Adult T-cell leukemia/lymphoma and cluster of HTLV-I associated diseases in Brazilian settings.

We studied the transmission routes of human T-cell lymphotropic virus type I (HTLV-I) within families of 82 Brazilian patients diagnosed with adult T-cell leukaemia/lymphoma (ATL). Diagnosis of ATL in 43 male and 39 female patients was based on clinical and laboratory criteria of T-cell malignancy and detection of HTLV-I monoclonal integration. Samples were tested for HTLV antibodies and infection was confirmed as HTLV-I by Western Blot and/or polymerase chain reaction (PCR) assays. Overall 26/37 (70%) of mothers, 24/37 (65%) of wives, 8/22 (36%) of husbands, 34/112 (30%) of siblings and 10/82 (12%) offspring were HTLV-I infected. In 11 ATL patients, mothers were repeatedly HTLV-I seronegative, but HTLV-I pol or tax sequences were detected in 2 out of 6 cases tested by PCR. ATL patients with seronegative mothers related the following risk factors for HTLV-I infection: 6 were breast-fed by surrogate mothers with unknown HTLV-I status, 4 had a sexually promiscuous behaviour and 1 had multiple blood transfusions at a young age. Familial aggregation of ATL and other HTLV-I associated diseases such as HTLV-I myelopathy (HAM/TSP) and or uveitis, ATL in sibling pairs or in multiple generations was seen in 9 families. There were 6 families with ATL and TSP sibling pairs. In 3 families at least one parent had died with lymphoma or presenting neurological diseases and 2 offspring with ATL. Further to the extent of vertical and horizontal transmission of HTLV-I infection within ATL families, our results demonstrate that mothers who provide surrogate breast-milk appear to be an important source of HTLV-I transmission and ATL development in Brazil.     

IL-2- and IL-2-R- independent proliferation of T-cell lines from adult T-cell leukemia/lymphoma patients

Human T-cell leukemia/lymphoma virus I (HTLV-I) is known to be associated with adult T-cell leukemia/lymphoma (ATL) as an etiological agent. The mechanism of leukemogenesis by HTLV, however, is still obscure. Two hypotheses have been proposed concerning abnormalities in IL-2 production and its receptor (Tac antigen) expression based on the experimental observations of IL-2-dependent ATL cell lines. In this study, we examine these hypotheses by using 3 leukemic T-cell lines from 3 Japanese patients with ATL. These cell lines were cultivated and established without addition of IL-2 to the culture medium. Cell-surface phenotype analysis by immunofluorescence with monoclonal antibodies (MAbs) and IL-2 binding assays revealed that one of the ATL cell lines, HPB-ATL-2, expresses only a minimal amount of IL-2 receptor (IL-2-R) on the cell surface and binds less radiolabelled human recombinant IL-2 than the other highly Tac-positive cell lines. Expression of Tac antigen in all ATL cell lines was not affected by IL-2, anti-Tac MAb or the tumor-promoter phorbol ester in the culture medium. The culture supernatant from these cell lines showed no IL-2 activity toward Con-A-stimulated human peripheral blood lymphocytes, and their growth was not affected by additional IL-2 in cultures. IL-2-independent growth and constitutive expression of its receptors on the cell surface were evident in our ATL cell lines. However, dense expression of IL-2 receptors was not essential for stimulation of leukemic proliferation of T cells by HTLV-I. Trans-activation of the PX40 gene product of HTLV-I for activation of IL-2-R gene might not be coincidentally associated with stimulation for cell proliferation.     

Serum level of soluble CD30 correlates with the aggressiveness of adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive disease with poor prognosis. CD30(+) cells are frequently observed in lymph node cells and peripheral blood mononuclear cells of ATL patients. In order to elicit the role of CD30(+) cells in ATL development, we investigated expression of the membrane type of CD30 (mCD30) and the soluble form of CD30 (sCD30) on ATL cells. Both mCD30 and sCD30 are expressed on various numbers of ATL cells in vivo as well as cell lines such as MT-2, L540 and Karpas 299. The level of serum sCD30 in each clinical stage showed an elevated level in patients with acute type (mean +/- standard error; 545.2 +/- 18.6 U/mL) rather than with lymphoma type ATL (327.62 +/- 94.85 U/mL). In four patients whose sera were stored and examined longitudinally, the levels decreased following the response to chemotherapy but not in patients with chemotherapy resistance. Thus, our results imply that sCD30 levels may be another useful marker for the activity and aggressiveness of ATL.     

Detection of adult T-cell leukemia-associated antigen in T-cell malignancies in the Nagasaki district of Japan

Adult T-cell leukemia-associated antigen (ATLA), a human retrovirus-associated antigen, and anti-ATLA antibodies were examined in 52 cases of T-cell malignancies in the Nagasaki district in southwestern Japan, which is known to be an ATL endemic area. These T-cell malignancies included 27 cases of ATL, 2 cases of T-cell chronic lymphocytic leukemia (T-CLL), 18 cases of T-cell lymphoma, and 5 cases of mycosis fungoides. Using the immunofluorescence method, ATLA-positive cells were detected in short-term mass culture of mononuclear cells from 22 of the 27 ATL patients, both T-CLL patients, 17 of 18 T-cell lymphoma patients, and 3 of the 5 mycosis fungoides patients. In an ATL patient in whom a high percentage of ATLA-positive cells were detected, many type C virus particles were observed in the extracellular space of the cultured mononuclear cells with an electron microscope. Sera from all 27 of the ATL patients, the 2 T-CLL patients, 15 of the 18 T-cell lymphoma patients, and 4 of the 5 mycosis fungoides patients were anti-ATLA antibody positive. These results indicate the possible participation of the retrovirus, ATL virus (ATLV), in these T-cell malignancies in ATL-endemic areas.     

Serum deoxythymidine kinase in adult T-cell leukemia-lymphoma and its related disorders

Serum deoxythymidine kinase (TK) was measured in 15 patients with the acute type of adult T-cell leukemia (ATL), in 4 with chronic ATL, in 10 with lymphoma type ATL, in 9 with pre-ATL, in 11 with human T-cell leukemia virus type I (HTLV-I) associated with myelopathy (HAM) and in 19 HTLV-I carriers. All these patients were positive for anti-HTLV antibody. The level of TK in pretreatment serum was highest in acute ATL (15.6-1600 U/l, median 107 U/l). It was elevated in chronic ATL (5.4-55.0 U/l, median 37.6 U/l) and lymphoma ATL (6.8-316 U/l, median 16.8 U/l) but normal in pre-ATL (1.8-4.7 U/l, median 2.8 U/l), HAM (1.2-6.0 U/l, median 3.0 U/l) and HTLV-I carriers (1.1-4.6 U/l, median 2.3 U/l). Statistical examination revealed a significant difference between the levels of acute ATL and chronic ATL/lymphoma ATL. In the patients of this series, a close correlation between the level of TK and lactic dehydrogenase (LDH) was statistically present (p less than 0.01). These facts indicate that TK level is a useful indicator of the aggressiveness of ATL cells.     

Differential methylation of class 1 histocompatibility antigen genes in T-cell lines derived from two different types of T-cell malignancies

We have previously shown that two human T-cell lines (HSB and 8402) derived from patients with childhood T-cell ALL (T-ALL) do not synthesize detectable mRNA for HLA-DR. The DR genes in both cell lines are hypermethylated relative to the same genes in T-cell lines infected with human T-cell leukemia virus (HTLV) and derived from patients with adult T-cell leukemia/lymphoma (ATL). These latter cell lines do express HLA-DR-mRNA, as well as HLA-DR surface antigens. We report here that the genes for HLA class I antigens are also highly methylated in the T-ALL T-cell lines relative to the same genes in the ATL T-cell lines, normal peripheral blood T cells, and autologous normal B-cell lines. In spite of substantial differences in the extent of methylation of class I-related genes, no obvious differences exist among these cell types in their levels of expression of HLA-A and -B antigens. The data clearly indicate, however, that the class I and class II components of the major histocompatability complex are unusually hypermethylated in several T-ALL-derived cell lines, while ATL T-cell lines do not substantially differ in this respect from normal peripheral blood T cells.