Increased microvessel density in involved organs from patients with HTLV-I associated adult T cell leukemia lymphoma

Adult T-cell leukemia-lymphoma (ATLL) is a rapidly progressive lymphoproliferative disorder secondary to infection with the human T cell lymphotropic virus type I (HTLV-I). The role of angiogenesis in the development and prognosis of many hematologic malignancies is established. We have previously shown that ATLL derived cells secrete high levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF), induce endothelial tube formation in vitro and establish functional gap junction-mediated communication with endothelial cells. We also demonstrated that plasma from ATLL and tropical spastic paraparesis/HTLV-I associated myelopathy patients exhibit very high levels of VEGF and b-FGF. Recently, we showed that treatment with the combination of zidovudine and interferon alpha reduced both HTLV-I proviral load and importantly VEGF plasma levels suggesting a potential anti-angiogenic effect of this therapy. In this report, we evaluated microvessel density (MVD) in involved organs from 20 patients with ATLL, as compared to normal organs from matched controls. We show evidence of significantly increased MVD in all tested involved organs from ATLL patients, suggesting that angiogenesis plays an important role in the development or organ invasion of ATLL, and could represent a potentially interesting target for anti-angiogenic therapy of ATLL.     

HTLV-I infection of T and B cells of a patient with adult T-cell leukemia-lymphoma (ATLL) and transmission of HTLV-I from B cells to normal T cells

We analysed the DNA of different tissues of a patient (HS) with adult T-cell leukemia/lymphoma virus (HTLV-I). We detected viral sequences in fresh specimens from spleen, thymus, liver, skin and peripheral blood neoplastic lymphocytes. The pattern of HTLV-I intergration is identical in the leukemic cells and in all other tissues analysed, but the signal intensity is strongest in the leukemic cells, indicating the source of HTLV-I proviral sequences was the leukemic T-cells which had infiltrated these tissues. In fact, the cultured skin fibroblasts of the patient did not contain HTLV-I sequence. However, cultured lymphocytes of this patient was consistently an immortalized B-cell line containing HTLV-I sequences in a manner indicative of a polyclonal infection. This cell line was also infected with the Epstein-Barr virus (EBV). In order to determine whether HTLV-I alone was sufficient for B-cell immortalization, we obtained single cell clones by limiting dilution. The DNA of all the cell clones that we analysed contained both the HTLV-I and EBV genomes, suggesting that immortalization of the B-cell was more likely due to the EBV rather than HTLV-I. Infectious HTLV-I viruses produced by the B-cell line still had the propensity to infect and transform T-lymphocytes in normal human umbilical cord blood. Unlike the parental B cells, the transformed T lymphocytes were clonally selected. Our results indicate that although the predominant infected cell population of the patient was his leukemic T lymphocytes, some of his EBV-positive B-lymphocytes were also polyclonally infected. The latter had a growth advantage in culture over the T lymphocytes but the virus produced by these immortalized B cells has not been adapted and has maintained its tropism for T cells.     

Cytological diagnosis of adult T‐cell leukemia/lymphoma in sputum

Adult T‐cell leukemia/lymphoma (ATLL) is a rare and often aggressive T‐cell leukemia/lymphoma that has been linked to infection by the human T‐cell lymphotropic virus type 1 (HTLV‐1). ATLL can involve multiple organs including the respiratory airway. A 53‐year‐old Trinidadian woman presented with productive cough and progressive shortness of breath. Her past medical history included duodenal strongyloidosis, skin rash, and hypercalcemia. Radiological studies showed increased interstitial markings. Sputum cytology showed atypical pleomorphic, small‐to‐medium‐sized, lobated lymphocytes with irregular and hyperchromatic nuclei resembling “flower cells” which were CD3±/CD20? by immunocytochemistry. A lung biopsy showed interstitial, peribronchiolar, and subpleural infiltration by a CD3±/CD25± atypical lymphocytic infiltrate. Together with peripheral blood findings and positive HTLV‐1 serology, the diagnosis of ATLL was made. We suggest that sputum evaluation in patients with ATLL risk factors can be diagnostic. Diagn. Cytopathol. 2016;44:416–418. © 2016 Wiley Periodicals, Inc.     

Pathophysiological significance of N‐myc downstream‐regulated gene 2 in cancer development through protein phosphatase 2A phosphorylation regulation

N‐myc downstream‐regulated gene 2 (NDRG2) is a candidate tumor suppressor in various cancers, including adult T‐cell leukemia/lymphoma (ATLL). NDRG2, as a stress‐responsive protein, is induced by several stress‐related signaling pathways and NDRG2 negatively regulates various signal transduction pathways. Although it has not been found to function alone, NDRG2 binds serine/threonine protein phosphatase 2A (PP2A), generating a complex that is involved in the regulation of various target proteins. The main function of NDRG2 is to maintain cell homeostasis by suppressing stress‐induced signal transduction; however, in cancer, genomic deletions and/or promoter methylation may inhibit the expression of NDRG2, resulting in enhanced tumor development through overactivated signal transduction pathways. A wide variety of tumors develop in Ndrg2‐deficient mice, including T‐cell lymphoma, liver, lung and other tumors, the characteristics of which are similar to those in Pten‐deficient mice. In particular, PTEN is a target molecule of the NDRG2/PP2A complex, which enhances PTEN phosphatase activity by dephosphorylating residues in the PTEN C‐terminal region. In ATLL cells, loss of NDRG2 expression leads to the failed recruitment of PP2A to PTEN, resulting in the inactivation of PTEN phosphatase with phosphorylation, ultimately leading to the activation of PI3K/AKT. Thus, NDRG2, as a PP2A adaptor, regulates the global phosphorylation of important signaling molecules. Moreover, the downregulation of NDRG2 expression by long‐term stress‐induced methylation is directly correlated with the development of ATLL and other cancers. Thus, NDRG2 might be important for the development of stress‐induced leukemia and other cancers and has become an important target for novel molecular therapies.     

Update on the therapy of highly aggressive non-Hodgkin’s lymphoma

This review focuses on the current understanding of the biology of highly aggressive non-Hodgkin’s lymphomas, such as Burkitt’s lymphoma, lymphoblastic lymphoma and adult T cell lymphoma/leukaemia. Specifically, this review will examine how our increased understanding of the pathophysiology of these diseases can be used to develop new therapies.     

Prolonged lymphocytosis as the first manifestation of Hodgkin-like adult T-cell leukemia/lymphoma

Hodgkin-like ATLL is a rare variant of adult T-cell leukemia/lymphoma (ATLL), a disease caused by human T-cell lymphotropic virus type-1 (HTLV-1). At admission, a 46-year-old female presented with lymphadenomegaly, lymphocytosis, slight elevation of LDH blood level, and acid-alcohol resistant bacilli in sputum and was being treated for pulmonary tuberculosis (Tb). She had lymphocytosis in the previous 20 months. Serology for HTLV-1 was positive. Lymph node was infiltrated by medium-sized lymphocytes with scattered Hodgkin and Reed-Sternberg-like cells CD30+, CS1-4+, and CD79a+. Background cells were CD4+ and CD25+. A clinical diagnosis of favorable chronic ATLL was given. She was treated with chemotherapy but later progressed to acute ATLL and ultimately died. Hodgkin-like ATLL should be considered in the histological differential diagnosis with Hodgkin lymphoma since treatment and prognosis of these diseases are distinct. It is also important to search for HTLV-1 infection in patients with unexplained prolonged lymphocytosis.     

A Cluster of Human T-lymphotropic Virus Type-I Carriers Found in the Southern District of Tokushima Prefecture

Since we had experience of eight patients with adult T-cellleukemia lymphoma from 130 cases of non-Hodgkin's lymphoma between1978 and 1986, a sero-epidemiological survey of anti human lymphotropicvirus type-I (HTLV-I) antibody was performed using a gelatinparticle agglutination test, an enzyme-linked immunosorbentassay and an indirect immunofluorescence assay for 2,190 adults(768 men and 1,422 women) aged between 21 and 86 years, in thesouthern district of Tokushima Prefecture. The inconclusivedata obtained using the above mentioned methods have been re-examinedby western blotting analysis using enzyme-labelled anti IgMand anti IgG. There was an overall prevalence rate of 6.0% (132/2,190)but higher rate were found in village C (10.9%) and villageD (14.2%). These two villages together with town K (6.1% sero-positive)form one community unit with a small population in a mountainarea, which could be prone to producing a cluster of HTLV-Icarriers. Town G with 8.0% sero-positivity is on the PacificOcean coast neighboring one of the endemic areas in the easternsection of Kohchi Prefecture. Interestingly, only IgM antibodywas detected in 17 of 137 carriers (13%), all females who hadnever had a blood transfusion, suggesting them to h ave beenin a sort of immunodeficient state, as reported in cases ofHTLV-I infection. In 13 of 29 HTIV-I carriers (44.8%) from villagesC and D, the viral antigen was detected in 1–9% (0.41±0.19%)of the peripheral blood mononuclear cells after being culturedwith phytohemagglutinin for three days. The data indicate thatthose carriers had evidently been infected with the HTIV-I virus.     

Inactivation of tumor suppressor genes and the progression of adult T-cell leukemia-lymphoma

Almost three decades have passed since adult T-cell leukemia-lymphoma (ATLL) was proposed as a new disease entity. During this period, its causative agent, human T-cell leukemia virus type-1 (HTLV-1), was found and a crucial role of the viral product Tax in the development of ATLL was disclosed. However, the long latent period after infection with HTLV-1 indicates the need for additional factors for full-blown ATLL, most of which are supposed to be provided by somatic mutations of cellular genes. Recent progress in cell-cycle research has revealed that the uncontrolled and superior proliferative activity of malignant cells is mainly caused by the breakdown of cell-cycle regulation and that most malignancies carry aberrations in p16-pRB and/or p53 pathways. ATLL is not an exception, despite the consistent association of HTLV-1 in primary leukemia cells, and accumulating evidence indicates that the breakdown of these pathways is indeed involved in the leukemogenesis of ATLL, especially in its later steps, which serve as the key events for promotion of indolent ATLL to aggressive ATLL.     

Significance of Postnatal Mother-to-Child Transmission of Human T-lymphotropic Virus Type-I on the Development of Adult T-cell Leukemia/Lymphoma

In order to shed light on the mode of HTLV-I infection by mother-to-child transmission, we examined sera of school children in a highly endemic town on two separate occasions at a 6-year interval. The carrier rates in ages 15–17, 8.7 and 2.1%, were significantly higher than that in ages 6–8, 1.7 and 0.4%, in studies. The latter survey showed a significantly lower carrier rate in each age group. Moreover, the carrier rates of those students born in 1965–1967 and 1968–1970 were stable in the interval. The data suggested that carrier rates of children at certian ages are reflected by the date of birth rather than by age. A prospective survey of children born of carrier mothers found the overall carrier rate to be approximately 25%, which did not increase with their age. There was no sexual difference in the carrier rate of children: 5/25 in male and 9/34 in females (χ² = 0.3). Carrier mothers could be separated into two groups: HTLV-I antigen-positive mothers and negative mothers. Nine out of 19 antigen-positive mothers (47%) and 2 of 19 antigen-negative mothers (11 %) had carrier children (χ² = 6.3). Twelve of 30 children born of antigen-positive carrier mothers (40%) were carriers, in contrast to 2 of 24 children (8%) of antigen-negative mothers (χ² = 7.8). Furthermore, 12 of 14 carrier children (86%) were of antigen-positive mothers. This suggests that postnatal but early transmission of HTLV-I plays a significant role in the maintenance of HTLV-I endemy and the development of adult T-cell leukemia/lymphoma.     

Adult T-cell leukemia/lymphoma in Jujuy,north-west Argentina

Human T-cell leukemia virus type 1 (HTLV-1) infection is prevalent in native Americans living in the Andes. Some of their malignant lymphomas (ML) show a peculiar histology suggestive of adult T-cell leukemia/lymphoma (ATLL). To determine whether ML resembling ATLL are indeed ATLL, re-analysis of 34 cases occurring in Jujuy, a province of Argentina, was conducted, concentrating on immunological phenotype, integration of HTLV-1 proviral DNA, expression of HTLV-1 p40Tax and p27Rex, and infection of Epstein-Barr virus (EBV). The ML were 22 cases of mature peripheral T-cell and natural killer (NK)-cell neoplasm (mT/NKN), 11 B-cell malignant neoplasms and one Hodgkin's lymphoma. Polymerase chain reaction against the HTLV-1 proviral DNA, using DNA extracted from paraffin sections, indicated integration of the HTLV-1 proviral DNA in three cases of eight mT/NKN. Two other cases of mT/NKN were positive for anti-HTLV-1 antibodies. Expression of p40Tax and p27Rex was detected in all five of these mT/NKN cases associated with HTLV-1. As such, these five mT/NKN were rediagnosed as ATLL. In situ hybridization signals for EBV-encoded small nuclear early region-1 were detected in nine cases of mT/NKN, of which five cases of NK-cell lymphoma were found to have cytoplasmic CD3 expression, a CD56 phenotype and positivity of TIA1. According to the new World Health Organization classification, the mT/NKN class includes five cases of ATLL and five cases of NK-cell lymphomas. The five cases of ATLL were of native American extraction from an HTLV-1-endemic area around Jujuy, north-west Argentina.