Adult T-cell Leukemia Cases Research Articles

Role of miRNAs in Human T Cell Leukemia Virus Type 1 Induced T Cell Leukemia: A Literature Review and Bioinformatics Approach.

Human T cell leukemia virus type 1 (HTLV-1) was identified as the first pathogenic human retrovirus and is estimated to infect 5 to 10 million individuals worldwide. Unlike other retroviruses, there is no effective therapy to prevent the onset of the most alarming diseases caused by HTLV-1, and the more severe cases manifest as the malignant phenotype of adult T cell leukemia (ATL). MicroRNA (miRNA) dysfunction is a common feature of leukemogenesis, and it is no different in ATL cases. Therefore, we sought to analyze studies that reported deregulated miRNA expression in HTLV-1 infected cells and patients’ samples to understand how this deregulation could induce malignancy. Through in silico analysis, we identified 12 miRNAs that stood out in the prediction of targets, and we performed functional annotation of the genes linked to these 12 miRNAs that appeared to have a major biological interaction. A total of 90 genes were enriched in 14 KEGG pathways with significant values, including TP53, WNT, MAPK, TGF-β, and Ras signaling pathways. These miRNAs and gene interactions are discussed in further detail for elucidation of how they may act as probable drivers for ATL onset, and while our data provide solid starting points for comprehension of miRNAs’ roles in HTLV-1 infection, continuous effort in oncologic research is still needed to improve our understanding of HTLV-1 induced leukemia.

Cytomegalovirus colitis presented with triserial longitudinal hemorrhage in an autopsy case of adult T-cell leukemia.

Longitudinal mucosal and submucosal hemorrhage along the taeniae coli is a potential colonic manifestation of cytomegalovirus infection in immunocompromised patients. When diagnosing cytomegalovirus colitis in immunocompromised patients, endoscopic biopsy on taeniae coli seems effective for viral detection.

Adult T-Cell Leukemia After Deceased Donor Liver Transplantation for Acute Liver Failure: A Case Report

Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL); however, the mechanism of its development has yet to be uncovered. A few ATL cases have been reported in HTLV-1-positive recipients after living donor liver transplantation. A 57-year-old HTLV-1-positive Japanese male suffered acute liver failure due to hepatitis B infection. He was transferred to our department to undergo deceased donor liver transplantation (DDLT). Tacrolimus and mycophenolate mofetil were induced for immunosuppression. His clinical outcome was satisfactory. However, he visited his physician 3 years after DDLT reporting abdominal pain and fever. A computed tomography scan showed multiple lymph node enlargement. Lymph node biopsy and his blood sample led to a diagnosis of ATL. He was transferred to the Department of Hematology and Oncology and underwent chemotherapy. To our knowledge, this is the first report of ATL development after DDLT from an HTLV-1-positive recipient. As is the case with our previous report, the current patient had undergone liver transplant for acute liver failure. Unlike living donor liver transplantation, however, DDLT needs no hepatic growth factor for liver regeneration. This finding sheds light on the resolution of the mechanism for the development of ATL from the HTLV-1 carrier.

H-104 ATL, ADF and human virus research

Prehistory of ATL Discovery and ADF/TRX. More than 40 years have passed since our initial description of peculiar cases of adult-onset leukemia with abnormal cells having multi-convoluted nuclei and T cellproperties, frequent in the southern regions of Japan in the early 1970s. In the initiation of Adult T-Cell Leukemia (ATL) research, both of my mentors Drs. Kimishige Ishizaka and Kiyoshi Takatsuki have been involved. Dr. Kiyoshi Takatsuki was a kind of hero of our medical school in B cell malignancy multiple myeloma and Heavy Chain Diseases. Dr. Kimishige Ishizaka, Discoverer of Immunoglobulin E (IgE) reaginic antibody, and Dr. Takatsuki had been working in the field of Immunoglobulin and myeloma proteins with great pioneers including late H Kunkel, and EF Osserman. Before my first description of ATL Cases with Dr. Takatsuki and the active instruction of late Dr. Toru Masuda in the Institute for Virus Res (IVR) of Kyoto Univ. returning from the Late Dr. L Herzenberg in Stanford Univ., I had been involved in the study of peculior myeloma-related disease, POEMS Syndrome/Takatsuki Disease/Crow-Fukase Syndrome. The POEMS Syndrome are characterized by polyneuropathy, organomegaly, endocrinopathy, myeloma protein, and skin changes. Drs. Y. Nishitani and Late M. Fukase in Kyoto Univ. also contributed in this Takatsuki Disease/Syndrome research. Indeed, Dr. Takatsuki was a kind of hero of our medical school in B cell malignancy multiple myeloma and HeavyChain Diseases, before ATL and HTLV. Retrospectively, the study of adult T cell leukemia (ATL) and the related virus HTLV-I was a forerunner for all of human retrovirology, in which AIDS and the related retrovirus HIV were identified a few years later in the 1980s. I remember the great contribution of late Dr. Yohei Ito, who had initiated the cooperative interaction between Kyoto and Dr. Gallo in NCI in 70's. Using the anti-TAC monoclonal antibody generated by the late Dr. Takashi Uchiyama, my close colleague, during his stay in Dr. T. A. Waldmann's laboratory in NIH Bethesda, a cDNA encoding IL-2Ra chain was cloned by our group in Kyoto and by Waldmann's group in Bethesda. Abnormal IL-2Ra chain expression and the IL-2 dependency of ATL cell lines greatly contributed to the study of leukemogenesis of ATL. A new soluble factor named ADF/ATL-derived factor was also detected in ATL cell lines. Dr. Michiyuki Maeda greatly contributed establishing many ATL cell lines with his green thumb. After years of study, ADF proved to be a first human counterpart of thiol-related oxido-reductase thioredoxin/TRX, which opened the field of redox regulation of cell signaling involved in a variety of diseases. Quite interestingly, TRX-family member protein, GIF/MIF involved in the IgE regulation was characterized by the group of Dr. K. Ishizaka who have moved from J. Hopkins Univ. Baltimore to La Jolla, LIAI. Close interaction among Drs. Kimishige Ishizaka, Kiyoshi Takastuki and T. A. Waldmanns before ATL and HTLV-I study was an essential base for our initiation of ATL research with late Takashi Uchiyama and many other close colleagues. I remember Dr. Gallo's helpful comment on the importance of the 3 Letter naming of ATL and ADF. In the therapeutic directions of ATL, monoclonal antibody seems to be still struggle: (1) Anti-Tac IL-2Ra Chain Therapies have been geared by TA Waldmann Group with many coworkers. However, the therapeutic effectiveness may be limited; (2) Anti-CCR4 mAbs applied to ATL cases by Dr. R Ueda Group in Japan is therapeutically effective. However high frequency of severe side effect namely Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis (SJS/TEN) have been reported. I may recall great contribution of late Drs. Takashi Uchiyama, Mitsuru Tsudo, Kazumasa Usami in Kyoto Univ. and Thomas Tursz of IGR Paris in our early ATL and ADF research. This paper is also dedicated for late Dr. Kimishige Ishizaka, discoverer of IgE and my great mentor close to Dr. Kiyoshi Takatsuki.

H-103 Clinical landscape of adult T-cell leukemia: Its impacts on hematology, virology, and immunology

Prof. Takatsuki and his colleagues reported adult T-cell leukemia (ATL) as the distinct clinical entity based on the clinical features including the presence of leukemic cells with characteristic nuclear shape (flower cells), skin lesion, hypercalcemia and frequent opportunistic infections, and mature T-cell immunophenotyped (Uchiyama T, et al, Blood, 1977). Importantly, they already predicted that ATL is caused by the pathogen since the birth places of ATL patients accumulated in the southwestern Japan (Kyushu and Okinawa). In 1980, Prof. Gallo and his colleagues reported the first human retrovirus, human T-cell leukemia virus (HTLV), from a patient with cutaneous T-cell lymphoma who was later diagnosed as ATL. Thereafter, it was established that HTLV causes ATL. Since Prof. Gallo found another human retrovirus, the first human retrovirus was named human T-cell leukemia virus type 1 (HTLV-1). Detection of anti-HTV-1 antibody enables us to identify HTLV infected individuals, which discloses unique distribution of HTLV-1carriers in Japan and the world. In addition, serological studies disclosed clinical landscape of ATL. Based on clinical features, ATL is classified to 4 clinical subtypes: acute, chronic, lymphoma-type and smoldering types (Yamguchi K, et al, Blood, 1983). In addition, the familial clustering of ATL cases was prominent, suggesting that genetic or virological factors are involved in development of ATL. Serological analyses found that HTLV-1 mainly transmits from male to female in horizontal transmission. Another clinical feature of ATL is the frequent spontaneous remission, which suggests immunological mechanism. Early studies of HTLV-1 focused on Tax, which not only transactivates viral genes transcription from the plus strand, but also influences cellular genes. However, Prof. Takatsuki's group thought that clinical ATL samples contain clue of leukemogenic mechanisms by HTLV-1. We found that Tax was not expressed in half of ATL cases, and 3 mechanisms of inactivation of Tax expression: deletion of 5′ long terminal repeat (LTR), DNA methylation of 5′LTR, and genetic changes of the tax gene (nonsense mutation, deletion and insertion), indicating that Tax is not necessary for maintenance of ATL (Tamiya S, et al, Blood, 1996). However, pX region and 3′LTR remain intact in all ATL cases, indicating that this region is critical for ATL. Thereafter, we showed that HTLV-1 bZIP factor (HBZ), which is encoded by the minus strand, plays critical roles for pathogenesis by HTLV-1. ATL is the first human disease caused by retrovirus. Tremendous efforts on HTLV-1 research by many researchers contribute to studies of next human retrovirus, human immunodeficiency virus (HIV). Thus, discovery of ATL in association with identification of causative human retrovirus leads to great contribution to medical science.

A-104 Tracing the intracellular journey of HTLV-1 HBZ during infection: From asymptomatic carriers to HAM/TSP ending to ATL: A one-way ticket?

HTLV-1 is the etiological agent of Adult T cell Leukemia (ATL) and of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) neurologic disorder. Although substantial progress has been made in understanding some cellular and molecular mechanisms underlying the pathology of the neoplastic and neurological diseases, still the intimate reason why some HTLV-1 infected patients develop HAM/TSP and others progress toward the neoplastic state are largely elusive. Two viral proteins, Tax-1 and HBZ, play an important role in both diseases. For example, Tax-1, the crucial transactivator needed for viral replication, has been implicated in the initiation but not in the maintenance of neoplastic process since leukemic cells may not express it. On the other hand, HBZ seems to be expressed throughout the infection and, importantly, is always expressed in leukemic cells. Nevertheless, the precise mechanism through which HBZ participates to initiation and/or maintenance of leukemic state is still unclear, as it is unclear the association of HBZ expression with initiation and/or maintenance of the inflammatory syndrome leading to HAM/TSP. Studies of this aspect have been partially prevented by the lack of suitable reagents to detect endogenous HBZ protein during the various phases of HTLV-1 infection and disease development. The recent isolation of a specific monoclonal antibody against HBZ, the 4D4-F3 mAb, by our group has allowed to precisely quantify and determine the subcellular distribution of the viral protein. We have demonstrated that HBZ, previously considered an exclusive nuclear protein, is mainly localized in the cytoplasm of PBMCs from HAM/TSP patients. Here, the analysis of a larger panel of patients has added new relevant informations on this point. PBMC from 13 HTLV-1 infected asymptomatic carriers (AC), 14 HAM/TSP and 4 ATL patients were analysed. Expression and subcellular distribution of endogenous HBZ and Tax-1 proteins were assessed by confocal microscopy with the 4D4-F3 and A51-2 mAbs, respectively. HBZ expression was confined to the cytoplasm of PBMC of HAM/TSP patients, appearing as discrete dots. The percentage of HBZ-positive cells ranged between 1% and 10% of total PBMC with the exception of one negative patient. Tax-1 was expressed in all HAM/TSP cases analyzed, ranging from 2% to 15% of total PBMC. Tax-1 was preferentially localized in the cytoplasm with fewer speckle-like dots in the nucleus. Interestingly, only in 1 case co-expression of HBZ and Tax-1 was observed in the same cells. In this unique case, however, although 8% and 15% of the cells were positive for HBZ and Tax-1, respectively, only 1% of cells co-expressed the 2 viral proteins. Of particular interest was the finding that PBMC of 6 out of 13 AC expressed HBZ (1%–4% of the cells) and again with an exclusive cytoplasmic localization. Tax-1 was expressed in 10 out of 13 cases (1%–11% of the cells). Only in 2 AC, HBZ and Tax-1 were found to be co-expressed in a very limited proportion of cells. The study of 4 distinct cases of ATL demonstrated, instead, that HBZ protein was expressed in the vast majority of the leukemic cells and importantly with an exclusive nuclear localization. Interestingly, none of these ATL cases were found to express Tax-1 protein. These results extend our previous observation on the dichotomy of HBZ localization between HAM/TSP and ATL, pointing to the exclusive either cytoplasmic or nuclear localization in the 2 diseased states, respectively. Moreover, they show a rather selective expression in distinct cells of either HBZ or Tax-1. The unprecedented observation that in AC, HBZ is expressed only in the cytoplasm strongly suggests a progressive modification of HBZ localization during the disease states associated to HTLV-1infection. Future studies will clarify whether the distinct HBZ intracellular localization is simply a marker or a causative event of disease evolution.

A case of adult T-cell leukemia (ATL) in which duodenal lesions appeared during treatment

A case of adult T-cell leukemia (ATL) in which duodenal lesions appeared during treatment

HTLV-1 bZIP factor suppresses TDP1 expression through inhibition of NRF-1 in adult T-cell leukemia

Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). We recently reported that abacavir, an anti-HIV-1 drug, potently and selectively kills ATL cells. This effect was attributed to the reduced expression of tyrosyl-DNA-phosphodiesterase 1 (TDP1), a DNA repair enzyme, in ATL cells. However, the molecular mechanism underlying the downregulation of TDP1 in ATL cells remains elusive. Here we identified the core promoter of the TDP1 gene, which contains a conserved nuclear respiratory factor 1 (NRF-1) binding site. Overexpression of NRF-1 increased TDP1-promoter activity, whereas the introduction of dominant-negative NRF-1 repressed such activity. Overexpression of NRF-1 also upregulated endogenous TDP-1 expression, while introduction of shNRF-1 suppressed TDP1 in Jurkat T cells, making them susceptible to abacavir. These results indicate that NRF-1 is a positive transcriptional regulator of TDP1-gene expression. Importantly, we revealed that HTLV-1 bZIP factor (HBZ) protein which is expressed in all ATL cases physically interacts with NRF-1 and inhibits the DNA-binding ability of NRF-1. Taken together, HBZ suppresses TDP1 expression by inhibiting NRF-1 function in ATL cells. The HBZ/NRF-1/TDP1 axis provides new therapeutic targets against ATL and might explain genomic instability leading to the pathogenesis of ATL.

Systemic diseases in patients with HTLV-1-associated uveitis

BackgroundHuman T-lymphotropic virus type 1 (HTLV-1) carriers may develop severe systemic diseases, such as adult T cell leukaemia (ATL) or HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This study aims to investigate...

Magnesium Level in Patients With Adult T-Cell Leukemia: A Case Report

Introduction: Adult T-cell leukemia (ATL) is a rare neoplasm of post-thymic lymphocytes observed in only 3% - 4% of patients infected with human T-lymphotropic virus (HTLV-1). The exact mechanism by which HTLV-1 triggers ATL is still under investigation. HTLV-I is endemic in specific regions of the world including Mashhad, Iran, where the present study was performed. Case Presentation: The current paper reports serum levels of calcium, magnesium and phosphorus as the main traced elements as well as parathormone (PTH) in five patients with ATL referred to Imam Reza hospital in Mashhad, Iran, in 2014. Conclusions:We observed upper limit values of the normal range forMgin the ATL cases whichmaynot be neglected from a clinical point of view. The other measurements did not show a remarkable difference with normal levels.

The Role of HBZ in HTLV-1-Induced Oncogenesis.

Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL) and chronic inflammatory diseases. HTLV-1 bZIP factor (HBZ) is transcribed as an antisense transcript of the HTLV-1 provirus. Among the HTLV-1-encoded viral genes, HBZ is the only gene that is constitutively expressed in all ATL cases. Recent studies have demonstrated that HBZ plays an essential role in oncogenesis by regulating viral transcription and modulating multiple host factors, as well as cellular signaling pathways, that contribute to the development and continued growth of cancer. In this article, I summarize the current knowledge of the oncogenic function of HBZ in cell proliferation, apoptosis, T-cell differentiation, immune escape, and HTLV-1 pathogenesis.

Identification of TIGIT as an HBZ-induced gene by genome-wide analyses: its association with evasion of host defense

Human T-cell leukemia virus type 1 (HTLV-1) is a causative virus of adult T-cell leukemia (ATL), and inflammatory diseases. HTLV-1 bZIP factor (HBZ) is encoded on the minus strand of HTLV-1, and expressed in all ATL cases. We performed RNA-seq and ChIP-seq using HBZ transduced T cells, and found that expressions of several Treg-related genes, including Foxp3, CD25, CCR4, CCR5, PD-1, NRP1, IKZF family genes, and T-cell immunoglobulin and ITIM domain receptor (Tigit), were upregulated by HBZ. We focused on TIGIT in this study. TIGIT expression was also upregulated in HTLV-1 infected cells in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients and CD4+ T cells of ATL patients. HBZ induced the histone modification of the promoter of TIGIT and enhanced its expression. HBZ also enhanced acetylation of H3K18, which is the specific target of p3. HBZ augments transcription of Tigit gene in the presence of PMA/Ionomycin stimulation. Although the detailed mechanism of HBZ mediated activation of Tigit transcription is still unclear, p3 and activated pathway by PMA/Ionomycin is likely involved in its regulation. Furthermore, we analyzed the function of Tigit in HBZ-expressing T cells and CD4+ T cells from HBZ-transgenic mice (HBZ-Tg), and found that stimulation of Tigit with its ligand, PVR, enhanced expression of inhibitory cytokines, such as IL-10, in HBZ-Tg. These results suggest that the enhanced Tigit expression by HBZ may play a key role to modulate the microenvironment where anti-tumor immune response is attenuated by increased expression of IL-10. This environment seems to be associated with the evasion of HTLV-1 infected cells from anti-tumor host immune response and the pathogenesis of HTLV-1 associated inflammatory diseases and ATL.

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.

Concomitant Administration of Gene-Modified T Cells Expressing a Chimeric CD16-CD3ζ Receptor with Mogamulizmab Synergistically Suppresses Adult T Cell Leukemia Cells in Vivo

[Background and purpose] Mogamulizumab, a newly developed monoclonal antibody (mAb) targeting the receptor for C-C chemokine 4 (CCR4) has initially demonstrated a promising clinical outcome for the treatment of therapy-resistant Adult T cell leukemia (ATL) of which tumor cells broadly express CCR4. However, in practice, we sometimes encounter unsuccessful cases of ATL treated with mogmulizumab, especially in the setting of combination therapy with multiple anticancer agents. In those cases, ATL tumor cells were still positive for CCR4, but the chemotherapy-induced lymphocytopenia was reproducibly noticeable. Considering the pharmacologic action of mogamulizumab, the defucosylation-enhanced antibody-dependent cellular cytotoxicity (ADCC) exerted by FcγRIIIa (CD16) expressing effector cells in vivo, as observed for Natural Killer (NK) cells, we hypothesized that adoptive transfer of ADCC effector cells might be able to regain the anti-ATL efficacy of mogamulizumab. Accordingly, we examined in vivo the feasibility of T cells gene-modified to express a newly generated chimeric CD16-CD3ζ receptor as a transferable alternative effector cell for mogamulizumab.[Methods] A novel affinity-matured chimeric CD16 with a 158V/V-CD3ζ (cCD16ζ ) gene construct was lentivirally introduced into CD3+ T cells from both healthy individuals (n=4) and patients with adult T cell leukemia (ATL) (n=3) (cCD16ζ-T cells). Using ATL or HTLV-1 infected cell lines variably expressing CCR4 on the cell surface (n=7), and primary ATL tumor cells (n=3), in the context of ADCC activity, functional properties of cCD16ζ-T cells were extensively examined both in vitro and in vivo, compared with those of NK cells from healthy donors (n=3). Next, we examined the in vivo therapeutic efficacy of concomitantly infused cCD16ζ-T cells with mogamulizumab via tail vein using a xenografted mouse model. Finally, we examined the feasibility of double gene-modified T cells to express human telomerase reverse transcriptase (hTERT)-specific TCR and cCD16ζ receptor, because we recently demonstrated that HLA-A*24:02-restricted and hTERT461-469 (VYGFVRACL)-specific TCR gene-modified CD8+ T cells displayed the cytocidal activity against ATL tumor cells (Blood, 2014).[Results] cCD16ζ-T cells were readily expandable in ex vivo culture using anti-CD2/CD3/CD28 beads and recombinant human (rh)IL-2, and they successfully displayed ADCC-mediated tumoricidal activity against CCR4+ MT-4 and ATN-1 (ATL cell lines) cells, but not CCR4- K562 cells with mogamulizumab, in a effector cell number and an antibody dose dependent manner. Pharmacological dose of 0.1μg/ml mogamulizumab could bind to ATL cell line cells expressing variable extent of CCR4 ranging from MFI 1.01 for HUT102 cell line to 12.3 for MT-2 (0.57 for K562 as a negative control), and could mediate the similar degree of ADCC activity exerted by cCD16ζ-T cells. The magnitude of ADCC activity mediated by cCD16ζ-T cells against opsonized ATN-1 with mogamulizumab was almost similar to that by activated NK cells using rhIL-2. This cytotoxicity was inhibited by anti-CD16 mAb. During ADCC, ligation of opsonized cancer cells with mogamulizumab to cCD16ζ receptor stimulated cCD16ζ-T cells to release toxic granules shown by CD107a expression. cCD16ζ-T cells generated from patients with ATL (n=3) successfully displayed ADCC activity against autologous tumor cells in vitro. Human cCD16ζ-T cells infused concomitantly with mogamulizumab synergistically inhibited the growth of disseminated luciferase gene-modified ATN-1 cells in immunodeficient mice, demonstrated using an in vivo bioluminescence assay. Additionally, this tumor suppressive effect contributed to the longer survival of treated mice. Finally, the double-gene modified CD3+ T cells could successfully recognize ATN-1 through both the mogamulizumab-opsonized CCR4 and hTERT epitope/HLA-A24*02 complex on the cell surface. DisclosuresOkamoto:CDM Center, Takara Bio Inc.: Employment. Mineno:Takara Bio Inc.: Employment. Shiku:Takara Bio Inc.: Research Funding.

Development of T cell lymphoma in HTLV-1 bZIP factor and Tax double transgenic mice.

Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). ATL cells possess a CD4+ CD25+ phenotype, similar to that of regulatory T cells (Tregs). Tax has been reported to play a crucial role in the leukemogenesis of HTLV-1. The HTLV-1 bZIP factor (HBZ), which is encoded by the minus strand of the viral genomic RNA, is expressed in all ATL cases and induces neoplastic and inflammatory disease in vivo. To test whether HBZ and Tax are both required for T cell malignancy, we generated HBZ/Tax double transgenic mice in which HBZ and Tax are expressed exclusively in CD4+ T cells. Survival was much reduced in HBZ/Tax double-transgenic mice compared with wild type littermates. Transgenic expression of HBZ and Tax induced skin lesions and T-cell lymphoma in mice, resembling diseases observed in HTLV-1 infected individuals. However, Tax single transgenic mice did not develop major health problems. In addition, memory CD4+ T cells and Foxp3+ Treg cells counts were increased in HBZ/Tax double transgenic mice, and their proliferation was enhanced. There was very little difference between HBZ single and HBZ/Tax double transgenic mice. Taken together, these results show that HBZ, in addition to Tax, plays a critical role in T-cell lymphoma arising from HTLV-1 infection.

Human T-cell leukemia virus type 1 and Foxp3 expression: viral strategy in vivo.

Human T-cell leukemia virus type 1 (HTLV-1) is the causal agent of adult T-cell leukemia (ATL) and inflammatory diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis, uveitis and infective dermatitis. However, it remains to be elucidated how HTLV-1 induces both neoplastic and inflammatory diseases. A critical component in the Treg-cell machinery is the transcription factor Forkhead box P3 (Foxp3), which is expressed in ~5% of CD4(+) T cells of healthy individuals. Foxp3 is expressed in around 80% of ATL cases. Recent studies point to the capacity of Treg cells to convert to other cell types, even to those with an inflammatory phenotype. These characteristics might indicate that Treg cells might be playing a critical role in HTLV-1 infection, either by being targeted by the virus or by regulating and modulating the immune response. In this review, we will discuss the interplay between Foxp3 expression and HTLV-1, focusing on important viral proteins that might help the virus to trigger the development of such diverse pathologies.

HTLV-1 bZIP Factor Suppresses Apoptosis by Attenuating the Function of FoxO3a and Altering Its Localization

As the infectious agent causing human adult T-cell leukemia (ATL), the human T-cell leukemia virus type 1 (HTLV-1) virus spreads in vivo primarily by cell-to-cell transmission. However, the factors that determine its transmission efficiency are not fully understood. The viral genome encodes the HTLV-1 bZIP factor (HBZ), which is expressed in all ATL cases and is known to promote T-cell proliferation. In this study, we investigated the hypothesis that HBZ also influences the survival of T cells. Through analyzing the transcriptional profile of HBZ-expressing cells, we learned that HBZ suppressed transcription of the proapoptotic gene Bim (Bcl2l11) and that HBZ-expressing cells were resistant to activation-induced apoptosis. Mechanistic investigations into how HBZ suppresses Bim expression revealed that HBZ perturbs the localization and function of FoxO3a, a critical transcriptional activator of the genes encoding Bim and also Fas ligand (FasL). By interacting with FoxO3a, HBZ not only attenuated DNA binding by FoxO3a but also sequestered the inactive form of FoxO3a in the nucleus. In a similar manner, HBZ also inhibited FasL transcription induced by T-cell activation. Further study of ATL cells identified other Bim perturbations by HBZ, including at the level of epigenetic alteration, histone modification in the promoter region of the Bim gene. Collectively, our results indicated that HBZ impairs transcription of the Bim and FasL genes by disrupting FoxO3a function, broadening understanding of how HBZ acts to promote proliferation of HTLV-1-infected T cells by blocking their apoptosis.

HTLV-1 bZIP factor supports proliferation of adult T cell leukemia cells through suppression of C/EBPα signaling.

BackgroundHuman T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus etiologically associated with adult T-cell leukemia (ATL). The HTLV-1 bZIP factor (HBZ), which is encoded by minus strand of provirus, is expressed in all ATL cases and supports the proliferation of ATL cells. However, the precise mechanism of growth promoting activity of HBZ is poorly understood.ResultsIn this study, we showed that HBZ suppressed C/EBPα signaling activation induced by either Tax or C/EBPα. As mechanisms of HBZ-mediated C/EBPα inhibition, we found that HBZ physically interacted with C/EBPα and diminished its DNA binding capacity. Luciferase and immunoprecipitation assays revealed that HBZ repressed C/EBPα activation in a Smad3-dependent manner. In addition, C/EBPα was overexpressed in HTLV-1 infected cell lines and fresh ATL cases. HBZ was able to induce C/EBPα transcription by enhancing its promoter activity. Finally, HBZ selectively modulated the expression of C/EBPα target genes, leading to the impairment of C/EBPα-mediated cell growth suppression.ConclusionHBZ, by suppressing C/EBPα signaling, supports the proliferation of HTLV-1 infected cells, which is thought to be critical for oncogenesis.

How human T-cell leukemia virus type 1 induces diseases

Human T-cell leukemia virus type1 (HTLV-1) is the causal agent of adult T-cell leukemia (ATL), and inflammatory diseases, such as HTLV-1 associated myelopathy (HAM), uveitis, alveolitis and infective dermatitis. Approximately, 5% of carrier will develop ATL after a long latent period. A characteristic of this virus is that HTLV-1 can transmit only by cell-to-cell contact. Therefore, HTLV-1 increases infected cells in vivo to facilitate its transmission. Previous studies suggest that Tax plays central roles in leukemogenesis by HTLV-1. However, Tax expression is frequently impaired in ATL cells. The HTLV-1 bZIP factor (HBZ) gene is transcribed from minus strand of provirus using 3’ long terminal repeat (LTR) as the promoter/ enhancer. Among ATL cases, only the HBZ gene is expressed in all ATL cases, suggesting an importance of the HBZ gene in ATL cells. Indeed, transgenic expression of the HBZ gene induced T-cell lymphoma and inflammatory diseases. Furthermore, regulatory T (Treg) cells increased in HBZ-transgenic (HBZ-Tg) mice. As a mechanism, HBZ induces transcription of the Foxp3 gene through enhanced Smad/ TGF-β pathway and converts infected cells to Treg cells. Concurrently, HBZ impairs function of Treg via interaction of HBZ with Foxp3 and associated factors. Thus, HBZ increases functionally impaired Treg cells in vivo, which resembles to phenotype of HTLV-1 infected cells and ATL cells. It is speculated that HTLV-1 infected Treg cells escape the host immune surveillance by acquired phenotype of Treg cells. Treg cells derived from HBZ-Tg mice progressively lost Foxp3 expression in vitro and produced IFN-γ, indicating that HBZ induces inflammation through unstable Foxp3 expression. Thus, HBZ is responsible for both T-cell lymphoma and inflammatory diseases. HBZ has pleiotropic functions as well as Tax. HBZ enhances TGF-β/Smad pathway while Tax inhibits it. Likewise, HBZ suppresses canonical NF-κB whereas Tax activates canonical and noncanonical NF-κB pathways. Thus, HBZ has opposite effects to Tax in many pathways. Interplay between HBZ and Tax likely coordinates to promote viral replication and proliferation of infected cells, leading to important roles in the pathogenesis.

A case of adult T-cell leukemia presenting primary Sjögren's syndrome-like symptoms

A case of adult T-cell leukemia presenting primary Sjögren's syndrome-like symptoms