Course Of Adult T-cell Leukemia Research Articles

Retinal manifestations in adult T-cell leukemia/lymphoma virus type 1 (HTLV-1)

To describe retinal manifestation throughout the course of adult T-cell leukemia (ATL) linked to infection by the human T-cell lymphotropic virus type-1 (HTLV-1). Retrospective case series of patients showing complicated ATL intraocular manifestation. Complete eye exam was performed, with among other test fluorescein angiography, indocyanine green angiography, and optical coherence tomography. Sample of the vitreous was collected for observation. Three patients showed intraocular complications linked to ATL, among the 175 ATL cases diagnosed in Martinique between 1983 and 2013. They were bilateral under retinal infiltrates associated with intermediate uveitis. In 2 cases, the ATL diagnosis was known. The retinal infiltrates visible through angiography allowed to make the ATL diagnosis for the third case. ATL type cells presence was confirmed in the vitreous for one patient. Despite chemotherapy, infiltrates progress in a centripetal pattern to reach the posterior pole. They were associated with vasculitis, thus reducing visual acuity to simple luminous perception. Retinal manifestation throughout ATL is very rare. From the onset of the disease, the presence of characteristic under retinal infiltrates allow right away the diagnosis of ATL for an HTLV-1 virus seropositive.

Human T-Cell Leukemia Virus Type 1 (HTLV-1) bZIP Factor Requires Cellular Transcription Factor JunD To Upregulate HTLV-1 Antisense Transcription from the 3′ Long Terminal Repeat

Infection with the human T-cell leukemia virus type 1 (HTLV-1) results in a variety of diseases including adult T-cell leukemia (ATL), a fatal malignancy characterized by the uncontrolled proliferation of virally infected CD4(+) T cells. The HTLV-1 basic leucine zipper factor (HBZ) is believed to contribute to development and maintenance of ATL. Unlike the other HTLV-1 genes, the hbz gene is encoded on the complementary strand of the provirus and therefore is not under direct control of the promoter within the 5' long terminal repeat (LTR) of the provirus. This promoter can undergo inactivating genetic or epigenetic changes during the course of ATL that eliminates expression of all viral genes except that of hbz. In contrast, repressive modifications are not known to occur on the hbz promoter located in the 3' LTR, and hbz expression has been consistently detected in all ATL patient samples. Although Sp1 regulates basal transcription from the HBZ promoter, other factors that activate transcription remain undefined. In this study, we used a proviral reporter construct deleted of the 5' LTR to show that HBZ upregulates its own expression through cooperation with JunD. Activation of antisense transcription was apparent in serum-deprived cells in which the level of JunD was elevated, and elimination of JunD expression by gene knockout or shRNA-mediated knockdown abrogated this effect. Activation through HBZ and JunD additionally required Sp1 binding at the hbz promoter. These data favor a model in which JunD is recruited to the promoter through Sp1, where it heterodimerizes with HBZ thereby enhancing its activity. Separately, hbz gene expression led to an increase in JunD abundance, and this effect correlated with emergence of features of transformed cells in immortalized fibroblasts. Overall, our results suggest that JunD represents a novel therapeutic target for the treatment of ATL.

JunD/HBZ enhances HBZ enhances HTLV-1 antisense transcription

Infection with the human T-cell leukemia virus type 1 (HTLV-1) results in a variety of diseases including adult T-cell leukemia (ATL), a fatal malignancy characterized by the uncontrolled proliferation of virally infected CD4+ T cells. The HTLV-1 basic leucine zipper factor (HBZ) is believed to contribute to development and maintenance of ATL. Unlike the other HTLV-1 genes, the hbz gene is encoded on the complementary strand of the provirus and therefore is not under direct control of the promoter within the 5' long terminal repeat (LTR) of the provirus. This promoter can undergo inactivating genetic or epigenetic changes during the course of ATL that eliminates expression of all viral genes except that of hbz. In contrast, repressive modifications are not known to occur on the hbz promoter located in the 3' LTR, and hbz expression has been consistently detected in all ATL patient samples. Although Sp1 regulates basal transcription from the HBZ promoter, other factors that activate transcription remain undefined. In this study, we used a proviral reporter construct deleted of the 5' LTR to show that HBZ upregulates its own expression through cooperation with JunD. Activation of antisense transcription was apparent in serum-deprived cells in which the level of JunD was elevated, and elimination of JunD expression by gene knockout or shRNA-mediated knockdown abrogated this effect. Activation through HBZ and JunD additionally required Sp1 binding at the hbz promoter. These data favor a model in which JunD is recruited to the promoter through Sp1, where it heterodimerizes with HBZ thereby enhancing its activity. Separately, hbz gene expression led to an increase in JunD abundance, and this effect correlated with emergence of features of transformed cells in immortalized fibroblasts. Overall, our results suggest that JunD represents a novel therapeutic target for the treatment of ATL.

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.

DNA Microarray Analysis of Stage Progression Mechanism in Adult T-Cell Leukemia.

Adult T-cell leukemia (ATL) is an intractable malignancy of peripheral CD4-positive T cells, in which human T-cell leukemia virus type I plays a pathological role. Clinical course of ATL can be subdivided into several phases; indolent “smoldering” and “chronic” stages, and aggressive “acute” stage. Individuals at the former usually undergo a stage progression toward the latter within several years, and ATL cells at the acute stage are highly refractory to current chemotherapeutic reagents. Molecular mechanisms underlying this stage progression are poorly understood yet. DNA microarray enables us to quantitate the mRNA amount for tens of thousands of genes simultaneously, and may provide novel insights into the pathogenesis as well as the stage progression mechanism of ATL. However, since the proportion of ATL cells within mononuclear cells (MNCs) of peripheral blood (PB) varies among different stages, it would be desirable to purify and directly compare ATL cells for an accurate profiling of gene expression. Given the fact that most PB MNCs are occupied by ATL cells in both chronic and acute stages, we purified CD4-positive T cells from PB of ATL individuals at chronic (n = 19) or acute (n = 22) stage. As a normal control, surface marker-matched T cells were purified from PB of healthy volunteers, and stimulated in vitro or not with PHA (n = 3 for each). A total of 47 specimens were thus subject to DNA microarray analysis with Affymetrix HGU133 A&B array sets, measuring the transcriptional level of ~33,000 human genes. Unsupervised hierarchical clustering based on the whole genes indicated that normal CD4-positive T cells, irrespective of PHA stimulation, had a molecular signature distinct from that of CD4-positive ATL cells, while the acute and chronic stages of ATL were not clearly separated from each other. Combination of a t-test (Welch's ANOVA, P<0.001) and an effect size selection (>150 U) identified 46 genes, expression of which contrasted the two clinical stages of ATL. Correspondence analysis of such stage-associated genes also demonstrated visually that both phases of ATL have a distinct molecular signature. Additionally, a very high accuracy was obtained by an artificial neural network in a trial of gene expression-based stage diagnosis. Further, we tried to screen, from our data set, novel “acute stage-specific gene markers”, resulting in the identification of a gene for a cytokine receptor. Intriguingly, the serum concentration of its ligand protein was elevated in ATL patients, especially at the acute stage. This autocrine loop for cell growth would be an interesting candidate for the transforming events which triggers the stage-progression in ATL, and also be a candidate for the targets of novel ATL therapies.

HTLV-1 Enhances Epstein-Barr Virus (EBV) Infectivity and EBV Infection Attributes to an Aggressive Organ Involvement in Adult T-Cell Leukemia.

The frequent involvement of adult T-cell leukemia (ATL) cells in organs such as the skin and lymph nodes is observed in ATL. Epstein-Barr virus (EBV) infection has been observed in the clinical course of ATL, and ATL cells in all skin cases were strongly positive for EBV nuclear antigen (EBNA)-1 and latent membrane protein (LMP)-1 by immunohistochemical staining. Interestingly, ATL cells in all skin cases were positive for CD45R0 (UCHL1) and CD20 (L26), indicating that they have both T and B cells characterization. We suggested that HTLV-1 enhances the entry of EBV into endothelial cells, epithelial cells and EBV presents for an active role of HTLV-1 in the development of ATL. Here, 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 B cell lines. On characterization of the cell lines, enhanced expression of intercellular adhesion molecule-1 or-3 (CD54, CD50), lymphocyte function-associated antigen-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) was observed compared to an EBV-infected B cell line, Raji. Moreover, EBV oncogenes such as EBV-encoded small RNA (EBER)-1, EBNA-1,-2 and LMP-2A were also detected. To investigate the role of the interaction of these viruses, we transfected EBV and/or HTLV-1 into a healthy donor's lymphocytes, Raji cells and a HTLV-1 negative T-cell line, Jurkat. Enhanced expression of adhesion molecules was observed in double transfectants (EBV and HTLV-1). Furthermore, we detected high production levels of interleukin-4 (IL-4) in those B-cell lines and transfectants. These results indicated co-expression of HTLV-1 and EBV may induce aggressive organ involvement by enhanced expression of adhesion molecules via IL-4 signaling. Furthermore, HTLV-1 could greatly enhance EBV infectivity and attribute to increased replication of EBV. EBV also could be a necessary cofactor for ATL development in immunodeficiency states. ATL patients who have been coinfected with EBV and HTLV-1 have a high risk of worse progress of disease. ATL patients have a poor treatment outcome, even with strong chemotherapy, especially who have severe skin involvements have a resistance for chemotherapy. Viewed from a different angle, our observations suggest that EBV infection may be used as one of bad prognostic factors and an identification of bad-risk patients who need to benefit from early high dose chemotherapy. Collectively, a reactivation of EBV infection and EBV oncogenes can provide an acceleration of organ involvement in ATL.These results can explain why EBV-associated ATL is more frequent and clinically more aggressive.

Observation of T Cell Surface Antigens in the Clinical Course of Adult T-Cell Leukemia: Case Report of a Spontaneous Remission

A patient with acute adult T-cell leukemia (ATL) in whom spontaneous remission was observed without any specific treatment having been given is described. The abnormal cell phenotype was CD4+, CD45RO+ and CD8-. As the number of abnormal cells decreased, CD4+ cell count decreased and CD8+ cells and CD45RA+ cells increased to normal levels (45 and 77%, respectively). Further, the number of cells with CD45RO antigen of intermediate fluorescence intensity increased. Five months after admission, we assessed the patient as being in a state of complete clinical remission; no abnormal cells were detected in peripheral blood, lymph node enlargement had disappeared and the serum chemistry was normal. When the abnormal cells in peripheral blood had disappeared, Southern blot analysis for HTLV-I proviral DNA still revealed a weak monoclonal band with EcoRI digestion, and HTLV-I proviral DNA was detected by polymerase chain reaction analysis. Thus, it appeared that very few abnormal cells persisted although the laboratory findings for ATL were normal. Our case could contribute to the understanding of the mechanism that underlies spontaneous remission in ATL.

Tax proteins of human T-cell leukemia virus type 1 and 2 induce expression of the gene encoding erythroid-potentiating activity (tissue inhibitor of metalloproteinases-1, TIMP-1).

A growth factor-like activity for erythroid cells (erythroid-potentiating activity) is produced by the T-cells infected with human T-cell leukemia virus type 2 (HTLV-2) (Gasson, J. C., Golde, D. W., Kaufman, S. E., Westbrook, C. A., Hewick, R. M., Kaufmann, R. J., Wong, G. G., Temple, P. A., Leary, A. C., Brown, E. L., Orr, E. C., and Clark, S. C. (1985) Nature 315, 768-771) and is reportedly identical with tissue inhibitors of matrix metalloproteinases-1 (TIMP-1) (Docherty, A. J. P., Lyons, A., Smith, B. J., Wright, E. M., Stephens, P. E., Harris, T. J. R., Murphy, G., and Reynolds, J. J. (1985) Nature 318, 66-69). We found that adult T-cell leukemia cell lines infected with HTLV-1 also express high levels of a TIMP-1 transcript. A viral transactivator of HTLV-1, Tax1, in a human T-cell line (Jurkat), was sufficient to stimulate transcription of the TIMP-1 gene. Deletion and mutation analysis of the TIMP-1 gene promoter showed that the AP-1 binding site in the 38-base pair sequence conserved between the human and mouse genes was essential for activation by Tax1. The transactivator of HTLV-2 also stimulated the promoter through the same cis-element. The reported growth-promoting activity of TIMP-1 against erythroid cells and potentially against HTLV-1-infected T-cells may modulate the clinical course of adult T-cell leukemia.

Exchange of dominant lymphoid cell clones in a patient with adult T-cell leukemia/lymphoma.

We performed a genotypic study on lymphoid cells from a patient with adult T-cell leukemia (ATL). Clonal proliferation of human lymphotropic virus type-1(HTLV-1)-infected helper T-cells was detected in the primary skin tumors, while no clonality of the virus-infected lymphocytes was observed in the peripheral blood. Following intensive chemotherapy, however, we detected the presence of two genotypically different HTLV-1-infected lymphocyte clones in different samples taken from the peripheral blood. These data demonstrated the exchange of the dominant neoplastic clone in the clinical course of ATL, suggesting the possibility that a certain clone among many repertoires of HTLV-1-infected T-cells has a capability of leukemogenesis, instead of the primary tumour cells.

Chromosomal Aberrations in Adult T Cell Leukemia: Relationship to the Clinical Severity

A chromosome study was performed in 18 patients with adult T cell leukemia (ATL), who were divided into three groups according to their clinical manifestations: nine had acute ATL, six had chronic ATL, and three had smoldering ATL. Mitotic cells were obtained from peripheral blood, lymph node, or bone marrow and were analyzed by the G-banding technique. In acute ATL, the chromosome number ranged from diploid or pseudodiploid to hyperdiploid; in the chronic type, from hypodiploid to hyperdiploid; but in the smoldering type, it was diploid. Eight of nine patients with acute ATL had trisomy 3 and/or trisomy 7, whereas none of those with chronic ATL exhibited these aberrations. Patients with smoldering ATL had a normal karyotype. The present findings indicate that the more aggressive the clinical course of ATL, the more complex the numerical and structural chromosome abnormality.

Chromosomal aberrations in adult T cell leukemia: relationship to the clinical severity

A chromosome study was performed in 18 patients with adult T cell leukemia (ATL), who were divided into three groups according to their clinical manifestations: nine had acute ATL, six had chronic ATL, and three had smoldering ATL. Mitotic cells were obtained from peripheral blood, lymph node, or bone marrow and were analyzed by the G-banding technique. In acute ATL, the chromosome number ranged from diploid or pseudodiploid to hyperdiploid; in the chronic type, from hypodiploid to hyperdiploid; but in the smoldering type, it was diploid. Eight of nine patients with acute ATL had trisomy 3 and/or trisomy 7, whereas none of those with chronic ATL exhibited these aberrations. Patients with smoldering ATL had a normal karyotype. The present findings indicate that the more aggressive the clinical course of ATL, the more complex the numerical and structural chromosome abnormality.