Influence of Epstein-Barr virus infection in adult T-cell leukemia

The involvement of adult T-cell leukemia (ATL) cells in organs such as the skin and lymph nodes is observed in about 50% of cases of ATL. Epstein-Barr virus (EBV) infection has often been observed in the clinical course of ATL. In this study, we established two B-cell lines from peripheral blood of patients with ATL. EBV DNA, proviral DNA for HTLV-1 and Tax mRNA were detected in both lines. As part of the characterization of these cells, an enhanced expression of intercellular adhesion molecule-1 (ICAM-1) (CD54) or ICAM-3 (ICAM-3) (CD50), lymphocyte function-1 (LFA-1) (CD11a/CD18), and Mac-1 (CD11b/CD18) was observed. To investigate the role of the interaction of these viruses, we transfected EBV and/or HTLV-1 into a healthy donor's lymphocytes, an EBV-infected B cell line, Raji, and a HTLV-1 negative T-cell line, Jurkat. Enhanced expression of adhesion molecules was also observed in double transfectants (EBV and HTLV-1). In the clinical course of ATL, LMP-1, EBNA-2, CD50 and CD54 were detected in lymph nodes and skin specimens by immunohistochemical staining. Furthermore, high levels of interleukin-4 (IL-4) were detected in these cell lines and transfectants. The results indicated that coinfection with HTLV-1 and EBV may induce aggressive organ involvement through the enhanced expression of adhesion molecules via IL-4 signaling. A new mechanism of ATL involvement is discussed.     

Clinicopathological studies of a patient with adult T-cell leukemia and pseudogynecomasty

We present a rare case of adult T cell leukemia/lymphoma (ATL) in which leukemic T cells expressed CD4 and CD25 surface antigens and infiltrated mammary glands during clinical course of the disease. A 40-year-old male was admitted with long-standing skin lesions and leukocytosis. Peripheral blood lymphocytes were highly pleomorphic and presented CD2, CD4, CD25, CD38 membrane surface antigens. The patient proved to be seropositive for human T-cell lymphotropic virus type I (HTLV-I) antibodies. Monoclonal expansion of lymphoid cells integrated with HTLV-I genome was observed, and the diagnosis of ATL chronic type was made. He underwent a chemotherapy regimen, and skin lesions and leukocytosis improved markedly. He progressed with an indolent clinical course of ATL, when he was admitted with bilateral hyperplasia of breast, recurrent skin lesions, and leukocytosis. Breast biopsy revealed bilateral gynecomasty, extensive leukemic infiltration of typical ATL cells in the mammary glands, and the presence of mammary epithelial cells productively infected with HTLV-I. This is the first report describing invasion of the mammary tissue with HTLV-I-transformed T-cells and HTLV-I-associated breast disease.     

CD20-positive adult T-cell leukemia.

A 67-year-old woman was admitted to our hospital because of lymphadenopathy and lymphocytosis. Monoclonal integration of HTLV-I provirus DNA was detected, and a diagnosis of adult T-cell leukemia (ATL) was made. Flow cytometry revealed that the ATL cells expressed CD20 as well as T-cell-associated antigens, and expression of CD20 mRNA was also demonstrated. A novel T-cell subpopulation expressing CD20 molecules has recently been identified. This is the first report of CD20-positive ATL, suggesting that HTLV-I can infect and transform CD20-positive T cells.     

Mutations of the p53 gene in adult T-cell leukemia.

The p53 tumor suppressor gene was examined by direct sequencing of polymerase chain reaction-amplified DNA from fresh tumor cells of 10 patients with adult T-cell leukemia (ATL). Samples included nine patients with acute or lymphomatous ATL, and one patient in whom samples were examined in both his acute and chronic stages of ATL. Four missense mutations and one silent point mutation in the coding region of the p53 gene were found in cells from five patients with either acute or lymphomatous ATL. The missense mutations were homozygous and occurred in evolutionarily highly conserved regions of p53. One patient had no p53 mutation in his leukemic cells during chronic phase of ATL, but had a homozygous point mutation at codon 273 (Arg to His) when he progressed to acute ATL. In summary, we show that p53 is frequently mutated in the acute phase of ATL and one informative case suggests that p53 mutations may be associated with the transition from chronic to acute ATL.     

Kaposi's sarcoma in human T-cell leukemia virus type I-associated adult T-cell leukemia

Kaposi's sarcoma (KS) developed in a patient with human T-cell leukemia virus type I (HTLV-I)-associated adult T-cell leukemia who was treated with a short-term course of monoclonal antibody immunotherapy. The presentation was transient and temporally related to the underlying clinical course. The association of KS in an HTLV-I infected, but not human immunodeficiency virus (HIV)-infected, individual should alert investigators to the occurrence of KS in retroviral-associated diseases other than acquired immunodeficiency disease syndrome. Recognition of the similarities and differences between HTLV-I and HIV infections may provide insights concerning the angiopathogenesis of KS.     

Existence of escape mutant in HTLV-I tax during the development of adult T-cell leukemia

Although Tax protein is the main target of cytotoxic T lymphocyte (CTL) on human T-cell lymphotropic virus type I (HTLV-I)-infected cells, and Tax peptide 11 through 19 binding to HLA-A*02 has been shown to elicit a strong CTL response, there are patients with adult T-cell leukemia (ATL) bearing HLA-A*02. To explore whether there is genetic variation in HTLV-I tax that can escape CTL recognition during the development of ATL, the HTLV-I tax gene was sequenced in 55 patients with ATL, 61 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and 62 healthy carriers, and it was correlated with the presence of HLA-A*02. First, a premature stop codon in the 5' half of the tax gene that looses transactivation activity on the viral enhancer was observed in 3 patients with acute and 1 patient with chronic ATL. This stop codon was revealed to emerge after the viral transmission to the patient from sequence analysis in family members with ATL. Second, amino acid change in Tax peptide 11-19 was observed in 3 patients with ATL. CTL assays demonstrated that this altered Tax 11-19 peptide, observed in ATL patients with HLA-A*02, was not recognized by Tax 11-19-specific CTL. Two patients with ATL had large deletions in tax by sequencing, and 5 patients with ATL had deletions in HTLV-I by Southern blotting. These findings suggest that at some stage of ATL development, HTLV-I-infected cells that can escape the host immune system are selected and have a chance to accumulate genetic alterations for further malignant transformation, leading to acute ATL.     

Familial adult T-cell leukemia/lymphoma

Clinical and laboratory data are described for two siblings who both developed adult T-cell leukemia/lymphoma resulting from infection by human T lymphotropic virus type I (HTLV-I). These findings suggest that genetic factors or virus-specific factors may determine which HTLV-I-infected individuals will develop leukemia.     

Chromosome studies in adult T-cell leukemia in Japan: significance of trisomy 7

Chromosomes were studied in cells from 15 japanese patients with adult T-cell leukemia (ATL). Mitoses were obtained from unstimulated peripheral blood in 12 patients and a lymph node in one patient. In two other patients, mitotic cells were obtained solely from peripheral blood stimulated with phytohemagglutinin (PHA). Chromsomally abnormal cells were seen in 14 of the 15 patients. The abnormal cells had a modal number of chromosomes in near diploid range in 12 patients, and in near triploid and tetraploid range in the remaining 2 patients, respectively. Eight of the nine patients analyzed by Q-banding had clonal chromosome abnormalities. The most common abnormality was trisomy no.7 or 7q, which was seen in 5 cases and has been primarily observed in lymphoid neoplasms. A 14q+ marker chromosome was found in two patients and a Dq+ in one patient; loss of a sex chromosome was found in three patients. Most chromosomes were involved in gains, losses, or structural rearrangements, but abnormalities of no. 11, which have been frequently found in lymphoid malignancies, was not observed in our series. The significance of these chromosome abnormalities is discussed.     

Human T-cell leukemia/lymphoma virus: the retrovirus of adult T-cell leukemia/lymphoma

Human T (thymus-derived)-cell leukemia/lymphoma virus (HTLV) is a new retrovirus first isolated from T-cell lines from a patient with cutaneous T-cell lymphoma from the southeastern United States. Closely related viruses have since been isolated from several patients with adult T-cell leukemia and lymphoma (and some normal persons) from different areas of the world. HTLV is not a genetically transmitted endogenous virus of humans, but it rather is acquired by postzygotic infection. Natural antibodies to several purified viral proteins have been observed in infected individuals. HTLV is transmissible in vitro to human cord blood T cells, and infection results in an increased growth rate, a reduced requirement for (and often independence from) T-cell growth factor, and an abrogation of the crisis period that usually occurs a month after the establishment of normal T-cell cultures. These data suggest that HTLV is the etiologic agent in some human cases of leukemia and lymphoma.