Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human T-cell leukemia virus type I (HTLV-I) is a causative virus of adult T-cell leukemia (ATL). ATL is a highly aggressive neoplastic disease of CD4 positive T lymphocyte, which is featured by the pleomorphic tumor cells with hypersegmented nuclei, called " flower cell". HTLV-I increases its copy number by clonal proliferation of the host cells, not by replication of the virus. Therefore, HTLV-I eventually induces ATL. Tax, encoded by HTLV-I pX region, has been recognized as a protein that plays a central role of the transformation of HTLV-I-infected cells by its pleiotropic actions. However, fresh ATL cells frequently lose Tax protein expression by several mechanisms. Recently, HBZ was identified in the complementary strand of HTLV-I and it is suggested that HBZ is a critical gene in leukemogenesis. Furthermore, there is a long latency period before onset of ATL, indicating the multistep mechanisms of leukemogenesis. Therefore, it is suggested that multiple factors, such as viral proteins, genetic and epigenetic changes of host genome, and immune status of the hosts, could be implicated in leukemogenesis of ATL.
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PMID:[HTLV-I and leukemogenesis]. 1744 73

Almost 30 years have passed since adult T-cell leukemia (ATL) was identified as a new disease entity in Japan. During this period, its causative agent, human T-cell leukemia virus (HTLV-1), was discovered, and a crucial role of the viral product Tax in ATL leukemogenesis was demonstrated. Recently, another HTLV-1 product, HBZ, which is encoded on the negative strand, was found, and it has now become a subject of intensive research because of its possible activity in cell proliferation. It is, however, impossible to elucidate the whole process of ATL leukemogenesis by studying only HTLV-1, and aberrations of cellular genes such as tumor suppressor genes are also profoundly involved in the later stages of ATL development. In contrast with the progress in the understanding of ATL pathogenesis, more progress in developing therapy for ATL is needed, and there has been only slight improvement in the prognosis. Recently, unique therapeutic approaches targeting molecules and/or mechanisms involved in the pathogenesis have been explored, and some of them produced encouraging results that might lead to breakthrough therapies. One of these approaches, the use of monoclonal antibody against chemokine receptor CCR4, is now ongoing as a multicenter clinical trial in Japan. Here we review the state of the art regarding our understanding of ATL leukemogenesis and new potential molecular targets in ATL therapy.
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PMID:The state of the art in the pathogenesis of ATL and new potential targets associated with HTLV-1 and ATL. 1802

Links between human T-cell leukemia virus type 1 and adult T-cell leukemia (ATL) were first suspected in 1980. Provirus integration has since been found in all ATL cells. Although the viral Tax protein is involved in the proliferation of the infected cells during the preleukemic stage, Tax expression is not systematically detected in primary leukemic cells. Recent studies found that the viral HBZ gene was always expressed in leukemic cells, suggesting its involvement in the progression of the infected cells toward malignancy. How could this new discovery be translated into possible new avenues for the prevention or treatment of ATL?
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PMID:Does the HBZ gene represent a new potential target for the treatment of adult T-cell leukemia? 1802 2

The human T-cell leukemia virus type 1 (HTLV-1) basic leucine zipper factor (HBZ) gene is encoded by the minus strand of the HTLV-1 provirus and transcribed from the 3' long terminal repeat (LTR). HBZ gene expression not only inhibits the Tax-mediated activation of viral gene transcription through the 5' LTR but also promotes the proliferation of infected cells. However, the HBZ promoter region and the transcriptional regulation of the gene have not been studied. In this study, we characterize the promoters of the spliced version of the HBZ gene (sHBZ) and the unspliced version of the HBZ gene (usHBZ) by luciferase assay. Both promoters were TATA-less and contained initiators and downstream promoter elements. Detailed studies of the promoter for the sHBZ gene showed that Sp1 sites were critical for its activity. The activities of the sHBZ and usHBZ gene promoters were upregulated by Tax through Tax-responsible elements in the 3' LTR. We compared the functions of the proteins derived from the sHBZ and usHBZ transcripts. sHBZ showed a stronger suppression of Tax-mediated transcriptional activation through the 5' LTR than did usHBZ; the level of suppression correlated with the level of protein produced. The expression of sHBZ had a growth-promoting function in a T-cell line, while usHBZ expression did not. This study demonstrates that Sp1 is critical for sHBZ transcription, which accounts for the constitutive expression of the sHBZ gene. Functional differences between sHBZ and usHBZ suggest that the sHBZ gene plays a significant role in the proliferation of infected cells.
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PMID:Transcriptional control of spliced and unspliced human T-cell leukemia virus type 1 bZIP factor (HBZ) gene. 1865 54

Human T-cell leukemia virus type 1 (HTLV-1) basic leucine zipper factor (HBZ) is dispensable for HTLV-1-mediated cellular transformation in cell culture, but is required for efficient viral infectivity and persistence in rabbits. In most adult T-cell leukemia (ATL) cells, Tax oncoprotein expression is typically low or undetectable, whereas Hbz gene expression is maintained, suggesting that Hbz expression may support infected cell survival and, ultimately, leukemogenesis. Emerging data indicate that HBZ protein can interact with cAMP response element binding protein (CREB) and Jun family members, altering transcription factor binding and transactivation of both viral and cellular promoters. Herein, lentiviral vectors that express Hbz-specific short hairpin (sh)-RNA effectively decreased both Hbz mRNA and HBZ protein expression in transduced HTLV-1-transformed SLB-1 T cells. Hbz knockdown correlated with a significant decrease in T-cell proliferation in culture. Both SLB-1 and SLB-1-Hbz knockdown cells engrafted into inoculated NOD/SCID(gammachain-/-) mice to form solid tumors that also infiltrated multiple tissues. However, tumor formation and organ infiltration were significantly decreased in animals challenged with SLB-1-Hbz knockdown cells. Our data indicate that Hbz expression enhances the proliferative capacity of HTLV-1-infected T cells, playing a critical role in cell survival and ultimately HTLV-1 tumorigenesis in the infected host.
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PMID:Human T-cell leukemia virus type-1 antisense-encoded gene, Hbz, promotes T-lymphocyte proliferation. 1868 44

Several studies have recently demonstrated the existence of human T-cell leukemia virus type 1 (HTLV-1) antisense transcripts, which allow the synthesis of the newly described HBZ protein. Although previous reports have been aimed at understanding the potential role of the HBZ protein in HTLV-1 pathogenesis, little is known as to how this viral gene is regulated. Here, using our K30-3'asLuc reporter construct, we show that the viral Tax protein upregulates antisense transcription through its action on the TRE sequences located in the 3' long terminal repeat. Generation of stable clones in 293T cells demonstrated that Tax-induced HBZ expression is importantly influenced by the integration site in the host genome. The cellular DNA context could thus affect the level of HBZ mRNA expression in infected cells.
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PMID:Upregulation of human T-cell leukemia virus type 1 antisense transcription by the viral tax protein. 1907 33

Human T-cell leukemia virus type 1 (HTLV-1) propagates in CD4 or CD8 T cells and, after extended latency periods of 30-50 years, causes a rapidly fatal leukemia called adult T-cell leukemia/lymphoma (ATL). Infection with HTLV-1 is also associated with a degenerative neuromuscular disease referred to as tropical spastic paraparesis or HTLV-1-associated myelopathy. HTLV genome, in addition to the structural proteins and retroviral enzymes, codes for a region at its 3' end originally designated pX. The products of this region (Tax, Rex, p12I, p13II, p30II and HBZ) play important roles in deregulation of cellular functions by either directly disrupting cellular factors or altering transcription of viral and cellular genes. Here, we will review current knowledge of protein-protein interactions that regulate transcriptional functions of proteins encoded by the pX region.
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PMID:Protein-protein interactions and gene expression regulation in HTLV-1 infected cells. 1927 40

Human T-lymphotropic virus type 1 (HTLV-1), the first known human retrovirus, induces various human diseases with a long latency period. The mechanism by which the virus causes diseases is still unknown. Studies indicate that viral replication is important at least for the development of HTLV-1 associated myelopathy, and therefore treatments based on our knowledge of human immunodeficiency virus type-1 (HIV-1) can be utilized to develop potent antiretroviral therapies targeting the replication enzymes reverse transcriptase, protease and integrase as well as the envelope glycoproteins. Furthermore, accessory gene products such as Tax and HBZ may also provide targets for chemotherapy. Treatment targeting these viral proteins may prevent the development of other HTLV-1-related diseases including adult T-cell leukemia, although such treatment may not be useful during the progression of the disease. This review describes the characteristics of HTLV-1 replication enzymes, envelope glycoproteins, and accessory proteins Tax and HBZ, and discusses the status of drug development strategies.
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PMID:Drug targets in human T-lymphotropic virus type 1 (HTLV-1) infection. 1927 4

Recently, HBZ has been reported to play an important role in the proliferation of adult T-cell leukaemia (ATL) cells and might be a target of novel therapy for ATL. To develop a novel immunotherapy for ATL, we verified the feasibility of cellular immunotherapy targeting HBZ. We established an HBZ-specific and HLA-A*0201-restricted cytotoxic T lymphocyte (CTL) clone. Detailed study using this CTL clone clearly showed that HBZ is certainly an immunogenic protein recognizable by human CTLs; however, HBZ-specific CTLs could not lyse ATL cells. Failure of HBZ-specific CTLs to recognize human T-cell leukemia virus type 1 (HTLV-1)-infected cells might be due to a low level of HBZ protein expression in ATL cells and resistance of HTLV-1-infected cells to CTL-mediated cytotoxicity. Although HBZ plays an important role in the proliferation of HTLV-1-infected cells, it may also provide a novel mechanism that allows them to evade immune recognition.
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PMID:HBZ is an immunogenic protein, but not a target antigen for human T-cell leukemia virus type 1-specific cytotoxic T lymphocytes. 1942 50

Telomerase activity, which has fundamental roles in development and carcinogenesis, strongly depends on the expression of human telomerase reverse transcriptase (hTERT), its catalytic subunit. In this report, we show that the basic helix-loop-helix factor, TAL1 (T-cell acute lymphoblastic leukemia 1), is a negative regulator of the hTERT promoter. Indeed, TAL1 overexpression leads to a decrease in hTERT mRNA abundance and hence to reduced telomerase activity. Conversely, suppression of TAL1 by RNA interference in Jurkat cells increases hTERT expression. Analysis by chromatin immunoprecipitation assays showed that TAL1 binds to the hTERT proximal promoter and recruits HDAC1. Considering the relationship recently established between TAL1 and the human T-cell leukemia virus type 1 (HTLV-1) Tax protein, which was confirmed in T lymphocyte clones derived from adult T-cell leukemia patients, we analyzed the effect of TAL1 with respect to the earlier characterized effects of Tax and HBZ (HTLV-1 basic leucine zipper) on hTERT expression. TAL1 was observed to reinforce the negative effect of Tax, whereas hTERT transactivation by the HBZ-JunD complex was repressed by TAL1 overexpression. Moreover, HBZ was found to induce proteasome-mediated degradation of TAL1. These observations support a model in which Tax and TAL1 by repressing hTERT would initially favor genomic instability, whereas expression of factors such as HBZ allows at a later stage an increase in hTERT production and consequently in telomerase activity.
Leukemia 2009 Nov
PMID:Inhibition of the hTERT promoter by the proto-oncogenic protein TAL1. 1958 3


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