Acute Myeloblasts Leukemia Associated with an Intermediate State Between the Healthy Carrier State and Adult T-cell Leukemia

This report describes an intermediate state between the human T-cell lymphotropic virus type I (HTLV-I) healthy carrier and adult T-cell Leukemia (ATL) who developed acute myeloblasts leukemia (AML, FAB subtype M2). The polyclonal integration of HTLV-I proviral DNA was demonstrated in the peripheral blood lymphoid cells, whereas AML cells had no HTLV-I proviral DNA. The patient achieved remission after combination chemotherapy but cells with lobulated nuclei persist at a low level and the polyclonal integration of HTLV-I proviral DNA is still demonstrated. We suggest that the patients with the integration of HTLV-I proviral DNA might develop secondary neoplasms more frequently than healthy carriers and this case stresses the need to exercise caution with these patients. The relationship between HTLV-I and AML is briefly discussed.     

Oral transmission of human T-cell leukemia virus type I in the rabbit

Four female rabbits were given twice-weekly oral inoculation of 2-4 X 10(7) cells from a male rabbit lymphoid cell line persistently infected with human T-cell leukemia virus type I (HTLV-I). After 8 weeks, one of them was found to be seroconverted for HTLV-I. Peripheral lymphocytes from the 4 rabbits were cultured in the presence of T-cell growth factor, and a lymphoid cell line with a normal female karyotype was established only from the seroconverted rabbit. This cell line was reactive with a monoclonal antibody to rabbit T-cells and expressed HTLV-I antigens and virus particles.     

Coexistence of acute monoblastic leukemia and adult T-cell leukemia: possible association with HTLV-I infection in both cases?

A 64 year-old Japanese man who developed acute monoblastic leukemia during the course of adult T-cell leukemia/lymphoma (ATL) was studied. Leukemic cells in the peripheral blood and bone marrow were monoblasts positive for alpha-naphthol butyrate esterase (alpha-NBE) staining, CD11c and CD36 antigens, whereas tumor cells in the pleural effusion were ATL cells positive for CD2, CD4, CD25, CD29 and CD45RA antigens. These two malignant cells had different chromosomal abnormalities. Monoclonal integration of human T-cell leukemia virus type I (HTLV-I) proviral DNA and T-cell receptor C beta gene (TCR C beta) rearrangement were detected in the ATL cells, but not in the leukemic monoblasts. By polymerase chain reaction (PCR) in the peripheral blood mononuclear cells (CD11c+ 98%, CD2+ 4%, CD20+ 0%) not containing ATL cells, the presence of the gag region of HTLV-I was confirmed. These facts indicate that a double positive T cell (CD29+, CD45RA+) was possibly the target cell for HTLV-I infection and that HTLV-I was not directly related to the oncogenesis of the monocyte lineage in the present case, even if it did infect the monocytes. However, there is still an outside possibility that HTLV-I induced acute monoblastic leukemia indirectly.     

Anti-human T-cell lymphotrophic virus type I antibody-positive adult T-cell leukemia/lymphoma with no monoclonal proviral DNA. A clinicopathologic and immunologic study

Proviral DNA of adult T-cell leukemia virus (HTLV-I) was examined by the standard Southern blotting method in lymph nodes of 45 patients with anti-HTLV-I antibody (ATLA)-positive adult T-cell leukemia/lymphoma (ATLL). Six of these patients revealed no monoclonal proviral HTLV-I DNA in tumor cells. These six patients showed typical flower cells in peripheral blood; they comprised five cases of the smoldering type and one of lymphoma type. They showed a longer clinical course than ATLL patients with integrated proviral HTLV-I DNA. Five of the six patients were alive from 8 to 36 months after onset; the other patient died 9 months after onset. Histologically, they exhibited features of T-cell malignancy but with absence of the typical cerebriform giant cells that are usually present in ATLL. The tumor cells represented T-cell markers, usually CD4, but CD25 was negative. Rearrangement of the T-cell receptor gene C beta was found in four of the six cases. On the basis of these results, cases of ATLL with no monoclonal proviral HTLV-I DNA should be clinicopathologically differentiated from those with integrated proviral DNA.     

Human T-cell leukemia virus type I associated lymphadenitis.

Histopathologic changes in lymph nodes were examined from ten patients with mild lymphadenopathy, a few atypical lymphocytes in their peripheral blood, skin lesions, and proviral DNA of human T-cell leukemia virus type I (HTLV-I) in their nodes. The proviral DNA of HTLV-I was detected by southern blot analysis, in situ hybridization, and/or polymerase chain reaction techniques. The lymph nodes showed preserved nodal architecture with diffuse infiltration of small to intermediate-sized lymphocytes in association with scattered transformed lymphocytes and a few immunoblast-like cells in the enlarged paracortex. The infiltrating lymphocytes were positive for CD4, but neither rearrangement nor deletion of T-cell receptors and immunoglobulin heavy chain genes was detected. Eight of ten patients received no therapy, and all patients were alive and healthy more than 5 months after the biopsies. The histologic findings resembled those of a viral infection and could be distinguished from HTLV-I associated lymphomas.     

Experimental inoculation of monkeys with autologous lymphoid cell lines immortalized by and producing human T-cell leukemia virus type-I

Cynomolgus monkeys and squirrel monkeys were inoculated with autologous lymphoid cell lines immortalized by and producing human T-cell leukemia virus type-I (HTLV-I) in order to serve as an animal model of adult T-cell leukemia (ATL). The autologous cell lines were established from peripheral blood mononuclear cells (PBMC) from each monkey by co-cultivation with lethally irradiated MT-2 cells producing HTLV-I. All of these cell lines, which had monkey karyotypes, grew continuously without addition of interleukin-2 (IL-2) and expressed virus-specific proteins of HTLV-I and IL-2 receptor. After inoculation with the autologous cell lines, specific antibodies against HTLV-I proteins could be detected in their plasma, and transformed HTLV-I-infected cells could be recovered from their peripheral blood for at least 6 months. However, no signs of ATL have been observed to data, i.e. 2 years after inoculation.     

Perinatal infection of human T-lymphotropic virus type I, the etiologic virus of adult T-cell leukemia/lymphoma. DNA amplification of specific human T-lymphotropic virus type I sequences

A gene amplification technique, polymerase chain reaction, was used to detect human T-lymphotropic virus type I (HTLV-I), the etiologic agent of adult T-cell leukemia/lymphoma, in mononuclear cells in peripheral blood and breast milk of ten HTLV-I carrier gravida. The DNA in umbilical cord blood mononuclear cells of the neonates born to the HTLV-I carrier gravida were also amplified and examined for the possibility of HTLV-I infection via placenta during pregnancy. The HTLV-I sequences were detected both in the peripheral blood and milk of all ten carrier gravida by Southern blot analysis of amplified DNA. However, HTLV-I proviral DNA could not be detected in the cord blood of the carriers' neonates, indicating that transplacental infection of HTLV-I should be rare and that postpartum infection via breast milk is a likely major perinatal transmission route.     

Human T-lymphotropic virus type I provirus and T-cell prolymphocytic leukemia

T-cell prolymphocytic leukemia (T-PLL) is a rare type of post-thymic T-cell neoplasm, the etiology of which is unknown. Patients with T-PLL have been found to be seronegative for human T-lymphotropic virus type-I (HTLV-I), and their leukemia cells do not retain monoclonally integrated HTLV-I provirus. Recently, we have demonstrated the presence of defective HTLV-I provirus by polymerase chain reaction in the DNA extracted from peripheral blood cells or affected lymph nodes of T-PLL patients. Although there is a possibility, from our observation, that an alternative mechanism is operating in HTLV-associated leukemogenesis, it is still unknown whether and how HTLV-I can contribute to the leukemogenesis of T-PLL. In this review, we describe controversial issues and discuss a role of HTLV-I in the leukemogenesis of T-PLL.     

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.     

Defective provirus form of human T-cell leukemia virus type I in adult T-cell leukemia/lymphoma: clinicopathological features

Human T-cell leukemia virus type I (HTLV-I) is associated with adult T-cell leukemia/lymphoma (ATLL). To examine the relationship between defective HTLV-I proviruses and clinicopathological features, we examined 95 patients with ATLL showing clonal integration of HTLV-I proviral DNA; 77 patients (81%) showed 1 clonal band, 15 (16%) showed 2 clonal bands, and 3 (3%) showed 3 clonal bands. In addition, the defective proviral form was detected in 28 patients (29%): 23 (30%) of the 77 with 1 clonal band, 4(27%) of the 15 with 2 clonal bands, and 1(33%) of the 3 with 3 clonal bands. The numbers of clonal bands had no association with the presence of defective proviruses. We classified the 95 patients with ATLL into four types according to clinicopathological features (smoldering leukemia, chronic leukemia, acute leukemia, and lymphoma types). The distribution of patients with the defective form was not different among these four types. The HTLV-I genomes must have integrated into the human genome DNA and been deleted partially in the cells. The defective form was kept during the clinical stage. All patients with the defective form showed defect of the gag or/and env region. No patient had a defect of the pX region. These data suggest that the pX region of HTLV-I must have played an important role in ATLL genesis.     

Oral transmission of human T-cell leukemia virus type-I into a common marmoset (Callithrix jacchus) as an experimental model for milk-borne transmission

To obtain experimental support for possible milk-borne infection of human T-cell leukemia virus type-I (HTLV-I), short-term-cultured viral antigen-positive lymphocytes obtained from peripheral blood of adult T-cell leukemia lymphoma complex (ATLL) patients were inoculated into the oral cavity of two adult common marmosets (Callithrix jacchus) in amounts comparable to those of HTLV-I-carrying cells fed to a baby in the milk of seropositive mothers. One of the animals seroconverted 2.5 months after the first inoculation. Cultures of peripheral blood mononuclear leukocytes of the marmoset revealed HTLV-I antigen expression in cells, indicating the establishment of oral infection of HTLV-I in an adult marmoset. The cell number deduced to be responsible for the infection was 5.6 X 10(7) cells (used in the first 2 inoculations). The results suggest that the concept of milk-borne infection of HTLV-I from a seropositive mother to her child is plausible.     

Successful bone marrow transplantation for adult T-cell leukemia from a donor with oligoclonal proliferation of T-cells infected with human T-cell lymphotropic virus.

We describe a patient who underwent successful BMT from her sibling for the treatment of adult T-cell leukemia/lymphoma. Pre-transplant examination of the donor revealed oligoclonal integration of HTLV-I proviruses within the germ line, and our concern was that clinical sequelae of HLTV-I infection might become evident in the setting of post-transplant immunosuppression. However, the patient has been in complete remission for 14 months after transplantation, and no clonality of HTLV-I provirus was detected in the peripheral blood cells using southern blotting analysis. Our experience supports the possibility of transplantation from HTLV-I positive donors.     

Transmission of HTLV-I to rabbits via semen and breast milk from seropositive healthy persons

Four rabbits inoculated intravenously with milk cells from 4 post-partum women seropositive for human T-cell leukemia virus type I (HTLV-I) and one rabbit inoculated with semen cells from a seropositive healthy man seroconverted for HTLV-I after 3-5 weeks but no seroconversion occurred in 2 rabbits inoculated with milk cells from a seronegative mother or with heated (56 degrees C, 30 min) milk cells from a seropositive mother. Attempts were made to isolate HTLV-I from peripheral blood lymphocytes harvested 5-15 weeks after cell inoculation and cultured in the presence of interleukin-2. An HTLV-I-carrying lymphoid cell line of rabbit origin was established from a rabbit inoculated with milk cells. Another long-term culture, derived from a rabbit inoculated with semen cells, also expressed HTLV-I antigens and harbored virus particles. Furthermore, transfusion of 20 ml of blood from all 5 seroconverted rabbits, but not from the 2 seronegative ones, caused seroconversion in normal recipient rabbits after 4-6 weeks.     

Chromosomal abnormalities in non-Hodgkin lymphoma with peripheral T-cell type: effect of HTLV-I infection

Cytogenetic studies were done in lymph node and peripheral leukemic cells from sixteen patients with non-Hodgkin lymphoma with peripheral T-cell type. Ten patients were positive for human T-cell leukemia virus I (HTLV-I) proviral DNA in tumour cells and six were negative. The former group had a higher tendency for leukemic conversion and poorer prognosis than the latter. However, no definite difference on the numerical and structural chromosomal abnormalities between these two groups was found. The most frequent chromosome abnormalities: 14p+, 14q+ and No. 6 abnormalities were detected in both groups. These results may indicate that HTLV-I does not play a specific role in chromosome abnormalities of non-Hodgkin lymphoma with peripheral T-cell type.     

Antigenicity of human T-cell leukemia virus-associated gp52: greater response in leukemia patients compared to healthy donors exposed to the virus

Monoclonal antibody HT462 recognizes a human T-cell leukemia virus type I (HTLV-I)-associated Mr 52,000 glycoprotein (HA-gp52), which is found on the surface of HTLV-infected cells. Whether HA-gp52 is encoded by the virus or by the infected cells has not yet been established. Using monoclonal HT462 in a competitive binding assay, natural human antibodies specific for HA-gp52 were detected in 97% of the patients from the United States, the Caribbean, and Japan with adult T-cell leukemia but not in healthy donors not exposed to HTLV-I. In contrast, antibodies to HA-gp52 occur in healthy virus-exposed donors, but at a lower prevalence than that observed in patients. Among Japanese from HTLV-I-endemic areas and exposed to the virus as indicated by the presence of antibodies to disrupted HTLV-I, 93% of adult T-cell leukemia patients were also seropositive for HA-gp52 compared to only 16% of healthy individuals. Differing sensitivities in the methods of assaying antibodies to HTLV and HA-gp52 were not responsible for these observations as shown by the lack of correlation of HTLV-I antibody titer with the presence of antibody to HA-gp52. Among adult T-cell leukemia patients, antibody titers to HTLV-I and HA-gp52 also varied independently. These results indicate that HA-gp52 in humans is antigenic and correlated with disease. Detection of antibody to this protein in asymptomatic individuals may be indicative of a predisease condition.     

Adult T-cell leukemia in spouses

A married couple who developed adult T-cell leukemia (ATL) is described. The husband presented with acute ATL and died soon after admission in spite of aggressive chemotherapy, and his wife, who is diagnosed as smoldering ATL, has been followed in the out-patient clinic. The couple had serum antibodies against human T-cell leukemia virus type I (HTLV-I) and the monoclonal integration of HTLV-I proviral DNA in their lymphocytes. The patients described represent the first reported example of ATL in a married couple.     

A B-cell line having chromosome 14 aberration at break band q11 derived from an adult T-cell leukemia patient

A B-cell line having translocations of chromosome 14 at break band q11 (the assigned locus of the alpha-chain gene of the T-cell antigen receptor) and chromosome 3 at break band p25 (the assigned locus of the c-raf-1 oncogene) was established from peripheral blood leukocytes of an adult T-cell leukemia (ATL) patient. The same chromosome 14 aberration at break band q11 and chromosome 3 aberration at break band p25 were also found in fresh T-cell leukemia cells. The B-cell line is surface immunoglobulin (sIg)+, immunoglobulin gene rearrangement+, ATL-specific antigen (ATLA)+, HTLV-1 proviral genome+, Epstein-Barr virus (EBV)-associated nuclear antigen (EBNA)+ and the EBV DNA genome+. The fresh T-leukemic cells were T-cell receptor gene rearrangement+, the HTLV-1 proviral genome+ and EBV DNA genome.     

IgG-κ-Type Plasmacytoma Secreting Salivary-Type Amylase in Adult T-Cell Leukemia

A IgG-κ-type plasmacytoma secreting salivary-type amylase ectopically is reported in a patient with smouldering adult T-cell leukemia(ATL). The patient had plasmacytomas in the distal region of the right femur, the proximal region of left tibia, and the left paranasal sinus. Both his serum and urine contained high levels of amylase. The presence of IgG-κ and S-type amylase in the plasmacytoma cells was confirmed immunocytochemically. In addition, he was also positive for the antibody against the human T-cell leukemia virus type I (HTLV-I), and had abnormal lymphocytes with convoluted nuclei(ATL cells) in the peripheral blood. The monoclonal integration of HTLV-I proviral DNA was demonstrated in the leukemic cells of the peripheral blood, but not in the plasmacytoma cells. Our case suggested that not only can HTLV-I infection play a role in the development of ATL, but may also induce a B-cell malignancy in an indirect manner, and even an ectopic amylase producing plasmacytoma.     

Adult T-cell leukemia: future prophylaxis and immunotherapy

A small population of human T-cell leukemia virus Type I (HTLV-I) carriers develop adult T-cell leukemia after a long incubation period. The results of a series of experiments using animal models suggest that insufficiency of HTLV-I-specific T-cell response induced by vertical HTLV-I infection allows enlargement of the HTLV-I-infected cell reservoir in vivo, a crucial risk factor of adult T-cell leukemia. In this review it is proposed that prophylactic Tax-targeted vaccines for the high-risk group of adult T-cell leukemia, which is characterized by low HTLV-I-specific T-cell response and high proviral load, can reduce the risk. Immunological studies on adult T-cell leukemia patients after hematopoietic stem cell transplantation also suggest that Tax-targeted immunotherapy may be effective against full-blown disease, although its indication may be limited.     

Adult T-cell leukemia: future prophylaxis and immunotherapy

A small population of human T-cell leukemia virus Type I (HTLV-I) carriers develop adult T-cell leukemia after a long incubation period. The results of a series of experiments using animal models suggest that insufficiency of HTLV-I-specific T-cell response induced by vertical HTLV-I infection allows enlargement of the HTLV-I-infected cell reservoir in vivo, a crucial risk factor of adult T-cell leukemia. In this review it is proposed that prophylactic Tax-targeted vaccines for the high-risk group of adult T-cell leukemia, which is characterized by low HTLV-I-specific T-cell response and high proviral load, can reduce the risk. Immunological studies on adult T-cell leukemia patients after hematopoietic stem cell transplantation also suggest that Tax-targeted immunotherapy may be effective against full-blown disease, although its indication may be limited.