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Zarei Ghobadi M, Emamzadeh R. Integration of gene co-expression analysis and multi-class SVM specifies the functional players involved in determining the fate of HTLV-1 infection toward the development of cancer (ATLL) or neurological disorder (HAM/TSP). PLoS One 2022; 17:e0262739. [PMID: 35041720 PMCID: PMC8765610 DOI: 10.1371/journal.pone.0262739] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 01/04/2022] [Indexed: 11/19/2022] Open
Abstract
Human T-cell Leukemia Virus type-1 (HTLV-1) is an oncovirus that may cause two main life-threatening diseases including a cancer type named Adult T-cell Leukemia/Lymphoma (ATLL) and a neurological and immune disturbance known as HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). However, a large number of the infected subjects remain as asymptomatic carriers (ACs). There is no comprehensive study that determines which dysregulated genes differentiate the pathogenesis routes toward ATLL or HAM/TSP. Therefore, two main algorithms including weighted gene co-expression analysis (WGCNA) and multi-class support vector machines (SVM) were utilized to find major gene players in each condition. WGCNA was used to find the highly co-regulated genes and multi-class SVM was employed to identify the most important classifier genes. The identified modules from WGCNA were validated in the external datasets. Furthermore, to find specific modules for ATLL and HAM/TSP, the non-preserved modules in another condition were found. In the next step, a model was constructed by multi-class SVM. The results revealed 467, 3249, and 716 classifiers for ACs, ATLL, and HAM/TSP, respectively. Eventually, the common genes between the WGCNA results and classifier genes resulted from multi-class SVM that also determined as differentially expressed genes, were identified. Through these step-wise analyses, PAIP1, BCAS2, COPS2, CTNNB1, FASLG, GTPBP1, HNRNPA1, RBBP6, TOP1, SLC9A1, JMY, PABPC3, and PBX1 were found as the possible critical genes involved in the progression of ATLL. Moreover, FBXO9, ZNF526, ERCC8, WDR5, and XRCC3 were identified as the conceivable major involved genes in the development of HAM/TSP. These genes can be proposed as specific biomarker candidates and therapeutic targets for each disease.
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Affiliation(s)
- Mohadeseh Zarei Ghobadi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Rahman Emamzadeh
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
- * E-mail: ,
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Wee Y, Liu Y, Zhao M. Identification of consistent post-translational regulatory triplets related to oncogenic and tumour suppressive modulators in childhood acute lymphoblastic leukemia. PeerJ 2021; 9:e11803. [PMID: 34316412 PMCID: PMC8286060 DOI: 10.7717/peerj.11803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 06/26/2021] [Indexed: 11/24/2022] Open
Abstract
Background Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer. It can be caused by mutations that turn on oncogenes or turn off tumour suppressor genes. For instance, changes in certain genes including Rb and p53 are common in ALL cells. Oncogenes and TSGs may serve as a modulator gene to regulate the gene expression level via their respective target genes. To investigate the regulatory relationship between oncogenes, tumour suppressor genes and transcription factors at the post translational level in childhood ALL, we performed an integrative network analysis on the gene regulation in the post-translational level for childhood ALL based on many publicly available cancer gene expression data including TARGET and GEO database. Methods We collected 259 childhood ALL-related genes from the latest online leukemia database, Leukemia Gene Literature Database. These 259 genes were selected from a comprehensive systematic literature with experimental evidences. The identified and curated genes were also associated with patient survival cases and we incorporated this pediatric ALL-related gene list into our analysis. We extracted the known human TFs from the TRRUST database. Among 259 childhood ALL-related genes, 101 unique regulators were mapped to the list of oncogene and tumour suppressor genes (TSGs) from the ONGene and the TSGene databases, and these included 74 TSGs, 62 oncogenes and 46 TF genes. Results The resulted regulation was presented as a hierarchical regulatory network with transcription factors (TFs) as intermediate regulators connecting the top modulators (oncogene and TSGs) to the common target genes. Cross-validation was applied to the results from the TARGET dataset by identifying the consistent regulatory motifs based on three independent ALL expression datasets. A three-layer regulatory network of consistent positive modulators in childhood ALL was constructed in which 74 modulators (40 oncogenes, 34 TSGs) are considered as the most important regulators. The middle layer and the bottom layer contain 34 TFs and 176 target genes, respectively. Oncogenes mostly participated in positive regulation of gene expression and the transcription process of RNA II polymerase, while TSGs were mainly involved in the negative regulation of gene expression. In addition, the oncogene-specific targets were enriched with regulators of the MAPK cascade while tumour suppressor-specific targets were associated with cell death. Conclusion The results revealed that oncogenes and TSGs possess a different functional regulatory pattern with regard to not only their biological functions but also their specific target genes in childhood ALL cancer progression. Taken together, our findings could contribute to a better understanding of the important regulatory mechanisms and this method could be used to analyse the targeted genes at the post-translational level in childhood ALL through integrative network analysis.
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Affiliation(s)
- YongKiat Wee
- School of Science and Engineering, University of the Sunshine Coast, Sunshine Coast, QLD, Australia
| | - Yining Liu
- The School of Public Health, Institute for Chemical Carcinogenesis, Guangzhou Medical University, Guangzhou, China
| | - Min Zhao
- School of Science and Engineering, University of the Sunshine Coast, Sunshine Coast, QLD, Australia
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Atabati H, Esmaeili SA, Allahyari A, Shirdel A, Rahimi H, Rezaee SA, Momtazi-Borojeni AA, Rafatpanah H. Evaluating mRNA expression of tax, B chain of PDGF and PDGF-β receptors as well as HTLV-I proviral load in ATL patients and healthy carriers. J Med Virol 2021; 93:3865-3870. [PMID: 32918495 DOI: 10.1002/jmv.26510] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 09/09/2020] [Accepted: 09/10/2020] [Indexed: 12/13/2022]
Abstract
Adult T-cell leukemia (ATL) is a life-threatening malignant neoplasm of CD4+ T cells resulted from human T-cell leukemia virus type I (HTLV-I). Tax1 protein of HTLV-I can induce malignant proliferation of T-cells by modulating the expression of growth factors such as platelet-derived growth factor (PDGF). Here, we aimed to investigate the proviral load (PVL) of HTLV-I in ATL and also to evaluate the mRNA expression of B chain of PDGF and PDGF-β receptors in ATL patients and HTLV-I-infected healthy carriers. To this end, peripheral blood mononuclear cells (PBMCs) were isolated by using Ficoll-Histophaque density centrifugation. The mean of HTLV-I PVL in ATL patients (42,759 ± 15,737 copies/104 cells [95% CI, 9557-75962]) was significantly (p = .01) higher than that in healthy carriers (650 ± 107 copies/104 cells [95% CI, 422-879], respectively. The HTLV-I PVL in ATL patients exhibited a significant correlation with PBMC count (R = .495, p = .001). The mRNA expression of Tax, B chain of PDGF, and PDGF-β receptor genes was significantly higher in healthy carriers than in patients with ATL. In conclusion, the expression of the canonical PDGFβ and its receptor, and their correlation with Tax expression cannot be a suitable indicator and/or prognostic factor for progression of ATL in HTLV-I carriers.
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Affiliation(s)
- Hadi Atabati
- Immunology Research Centre, Division of Inflammation and Inflammatory Diseases, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed-Alireza Esmaeili
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abolghasem Allahyari
- Department of Internal Medicine, Imam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abbas Shirdel
- Department of Internal Medicine, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Rahimi
- Department of Internal Medicine, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Abdolrahim Rezaee
- Immunology Research Centre, Division of Inflammation and Inflammatory Diseases, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir A Momtazi-Borojeni
- Halal Research Center of IRI, FDA, Tehran, Iran
- Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Houshang Rafatpanah
- Immunology Research Centre, Division of Inflammation and Inflammatory Diseases, Mashhad University of Medical Sciences, Mashhad, Iran
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Ye Y, Ding N, Mi L, Shi Y, Liu W, Song Y, Shu S, Zhu J. Correlation of mutational landscape and survival outcome of peripheral T-cell lymphomas. Exp Hematol Oncol 2021; 10:9. [PMID: 33546774 PMCID: PMC7866778 DOI: 10.1186/s40164-021-00200-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 01/20/2021] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVE To explore the correlation of mutation landscape with clinical outcomes in patients with peripheral T-cell lymphoma (PTCL). METHODS We retrospectively analyzed the clinicopathological and prognosis data of 53 patients with PTCL from November 2011 to December 2017. Targeted next-generation sequencing of a 659-gene panel was performed for tissues from 53 patients with PTCLs. The correlation of mutation landscape with clinical outcomes was analyzed. RESULTS TET2 was the most frequently mutated gene (64%), followed by RHOA (43%), PCLO (23%), DNMT3A (19%), IDH2 (17%), PIEZO1 (17%) and TP53 (15%). When mutated genes were categorized into functional groups, the most common mutations were those involved in epigenetic/chromatin modification (75%), T-cell activation (74%), and the DNA repair/TP53 pathway (64%). TET2/TP53 mutations were significantly associated with positive B symptoms (P = 0.045), and elevated lactate dehydrogenase (LDH) level (P = 0.011). Moreover, TET2/TP53 mutation was a risk factor for PTCL patient survival (HR 3.574, 95% CI 1.069 - 11.941, P = 0.039). The occurrence of JAK/STAT pathway mutations in angioimmunoblastic T-cell lymphoma (AITL) patients conferred a worse progression-free survival (HR 2.366, 95% CI 0.9130-6.129, P = 0.0334). CONCLUSIONS Heterogeneous gene mutations occur in PTCL, some of which have a negative impact on the survival outcome.
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Affiliation(s)
- Yingying Ye
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, Haidian District, No 52, Fucheng Road, Beijing, 100142, China
| | - Ning Ding
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, Haidian District, No 52, Fucheng Road, Beijing, 100142, China
| | - Lan Mi
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, Haidian District, No 52, Fucheng Road, Beijing, 100142, China
| | - Yunfei Shi
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Haidian District, No 52, Fucheng Road, Beijing, 100142, China
| | - Weiping Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, Haidian District, No 52, Fucheng Road, Beijing, 100142, China
| | - Yuqin Song
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, Haidian District, No 52, Fucheng Road, Beijing, 100142, China
| | - Shaokun Shu
- Department of Biomedical Engineering, Peking University, Beijing, 100871, China.
| | - Jun Zhu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, Haidian District, No 52, Fucheng Road, Beijing, 100142, China.
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Choudhuri J, Geiser Roberts L, Zhang Y, Wang Y, Fang Y. A Rare CD4-CD8+ Adult T-Cell Leukemia/Lymphoma with Unique Molecular Mutations: A Case Report with Literature Review. Case Rep Hematol 2020; 2020:8890502. [PMID: 33178468 PMCID: PMC7647743 DOI: 10.1155/2020/8890502] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 10/15/2020] [Accepted: 10/19/2020] [Indexed: 11/18/2022] Open
Abstract
Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell neoplasm caused by infection of the human T-cell lymphotropic virus type 1 (HTLV-1). Most ATLL cases are CD4-positive and CD8-negative. Though rare, there are a few dual negative (CD4-CD8-), dual positive (CD4+CD8+), and CD4-CD8+ cases reported in literature. ATLL is associated with HTLV-1 infection, but HTLV-1 alone cannot cause the malignant transformation of infected T cells. Additional genetic and/or epigenetic events are required for the development of the disease. Here, we report an unusual CD4-CD8+ATLL in a 76-year-old male with a unique molecular genetic profile. Molecular studies revealed alterations in 10 genes. Three of them are predicted to be pathogenic by the computational models, including the frameshift change in ZFHX4 and missense mutations in RHOA and POT1. The specific mutations of POT1 (c.281A > G; p.Q94R), RHOA (c.47G > A; p.C16Y), and ZFHX4 (c.2871delC; p.F958Sfs ∗ 31) have never been previously reported in ATLL to the best of our knowledge. The clinical significance of other genetic alterations is unknown. Further research is warranted to correlate this patient's molecular findings with other ATLL cases. Correlation specifically with other cases of CD8+ ATLL could prove to be useful in understanding the pathogenesis of this rare variant of an already rare form of leukemia/lymphoma.
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Affiliation(s)
- Jui Choudhuri
- Department of Pathology, Montefiore Medical Center, Bronx, New York City 10467, NY, USA
- Albert Einstein College of Medicine, Pelham PKWY South Bronx, New York City 10467, NY, USA
| | - Leah Geiser Roberts
- Liberty University College of Osteopathic Medicine (LUCOM), Lynchburg, VA, USA
| | - Yan Zhang
- Albert Einstein College of Medicine, Pelham PKWY South Bronx, New York City 10467, NY, USA
- Jacobi Medical Center and NCB Hospital, Bronx, New York City 10467, NY, USA
| | - Yanhua Wang
- Department of Pathology, Montefiore Medical Center, Bronx, New York City 10467, NY, USA
- Albert Einstein College of Medicine, Pelham PKWY South Bronx, New York City 10467, NY, USA
| | - Yanan Fang
- Department of Pathology, Montefiore Medical Center, Bronx, New York City 10467, NY, USA
- Albert Einstein College of Medicine, Pelham PKWY South Bronx, New York City 10467, NY, USA
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Mui UN, Haley CT, Tyring SK. Viral Oncology: Molecular Biology and Pathogenesis. J Clin Med 2017; 6:E111. [PMID: 29186062 PMCID: PMC5742800 DOI: 10.3390/jcm6120111] [Citation(s) in RCA: 117] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 11/17/2017] [Accepted: 11/22/2017] [Indexed: 02/06/2023] Open
Abstract
Oncoviruses are implicated in approximately 12% of all human cancers. A large number of the world's population harbors at least one of these oncoviruses, but only a small proportion of these individuals go on to develop cancer. The interplay between host and viral factors is a complex process that works together to create a microenvironment conducive to oncogenesis. In this review, the molecular biology and oncogenic pathways of established human oncoviruses will be discussed. Currently, there are seven recognized human oncoviruses, which include Epstein-Barr Virus (EBV), Human Papillomavirus (HPV), Hepatitis B and C viruses (HBV and HCV), Human T-cell lymphotropic virus-1 (HTLV-1), Human Herpesvirus-8 (HHV-8), and Merkel Cell Polyomavirus (MCPyV). Available and emerging therapies for these oncoviruses will be mentioned.
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Affiliation(s)
- Uyen Ngoc Mui
- Center for Clinical Studies, Houston, TX 77004, USA.
| | | | - Stephen K Tyring
- Center for Clinical Studies, Houston, TX 77004, USA.
- Department of Dermatology, University of Texas Health Science Center at Houston, Houston, TX 77004, USA.
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Molecular Highlighting Analysis of Mutational P27 Gene Products in Association with Human T-lymphotropic (HTLV-1) Infection in Tissues from Iraqi Patients with Non-Hodgkin’s lymphoma. JOURNAL OF PURE AND APPLIED MICROBIOLOGY 2017. [DOI: 10.22207/jpam.11.3.24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Madapura HS, Salamon D, Wiman KG, Lain S, Klein E, Nagy N. cMyc-p53 feedback mechanism regulates the dynamics of T lymphocytes in the immune response. Cell Cycle 2017; 15:1267-75. [PMID: 26985633 DOI: 10.1080/15384101.2016.1160975] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
Activation and proliferation of T cells are tightly regulated during the immune response. We show here that kinetics of proliferation of PHA activated T cells follows the expression of cMyc. Expression of p53 is also elevated and remains high several days after activation. To investigate the role of p53 in activated T cells, its expression was further elevated with nultin-3 treatment, a small molecule that dissociates the E3 ubiquitin protein ligase MDM2 from p53. Concomitantly, cMyc expression and proliferation decreased. At the other end of the cMyc-p53 axis, inhibition of cMyc with 10058-F4 led to down regulation of p53, likely through the lower level of cMyc induced p14ARF, which is also known to dissociate the p53-MDM2 complex. Both compounds induced cell cycle arrest and apoptosis. We conclude that the feedback regulation between cMyc and p53 is important for the T cell homeostasis. We also show that the two compounds modulating p53 and cMyc levels inhibited proliferation without abolishing the cytotoxic function, thus demonstrating the dichotomy between proliferation and cytotoxicity in activated T cells.
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Affiliation(s)
- Harsha S Madapura
- a Department of Microbiology , Tumor and Cell Biology, Karolinska Institutet , Stockholm , Sweden.,b Department of Oncology-Pathology , Cancer Center Karolinska (CCK), Karolinska Institutet , Stockholm , Sweden
| | - Daniel Salamon
- a Department of Microbiology , Tumor and Cell Biology, Karolinska Institutet , Stockholm , Sweden
| | - Klas G Wiman
- b Department of Oncology-Pathology , Cancer Center Karolinska (CCK), Karolinska Institutet , Stockholm , Sweden
| | - Sonia Lain
- a Department of Microbiology , Tumor and Cell Biology, Karolinska Institutet , Stockholm , Sweden
| | - Eva Klein
- a Department of Microbiology , Tumor and Cell Biology, Karolinska Institutet , Stockholm , Sweden
| | - Noémi Nagy
- a Department of Microbiology , Tumor and Cell Biology, Karolinska Institutet , Stockholm , Sweden
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Akbarin MM, Shirdel A, Bari A, Mohaddes ST, Rafatpanah H, Karimani EG, Etminani K, Golabpour A, Torshizi R. Evaluation of the role of TAX, HBZ, and HTLV-1 proviral load on the survival of ATLL patients. Blood Res 2017; 52:106-111. [PMID: 28698846 PMCID: PMC5503887 DOI: 10.5045/br.2017.52.2.106] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2016] [Revised: 02/15/2017] [Accepted: 03/14/2017] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy with very poor prognosis and short survival, caused by the human T-lymphotropic virus type-1 (HTLV-1). The HTLV-1 biomarkers trans-activator x (TAX) and HTLV-1 basic leucine zipper factor (HBZ) are main oncogenes and life-threatening elements. This study aimed to assess the role of the TAX and HBZ genes and HTLV-1 proviral load (PVL) in the survival of patients with ATLL. METHODS Forty-three HTLV-1-infected individuals, including 18 asymptomatic carriers (AC) and 25 ATLL patients (ATLL), were evaluated between 2011 and 2015. The mRNA expression of TAX and HBZ and the HTLV-1 PVL were measured by quantitative PCR. RESULTS Significant differences in the mean expression levels of TAX and HBZ were observed between the two study groups (ATLL and AC, P=0.014 and P=0.000, respectively). In addition, the ATLL group showed a significantly higher PVL than AC (P=0.000). There was a significant negative relationship between PVL and survival among all study groups (P=0.047). CONCLUSION The HTLV-1 PVL and expression of TAX and HBZ were higher in the ATLL group than in the AC group. Moreover, a higher PVL was associated with shorter survival time among all ATLL subjects. Therefore, measurement of PVL, TAX, and HBZ may be beneficial for monitoring and predicting HTLV-1-infection outcomes, and PVL may be useful for prognosis assessment of ATLL patients. This research demonstrates the possible correlation between these virological markers and survival in ATLL patients.
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Affiliation(s)
- Mohammad Mehdi Akbarin
- Inflammation and Inflammatory Diseases Research Center, Faculty of Medicine, Mashhad University of Medical sciences, Mashhad, Iran
| | - Abbas Shirdel
- Hematology Department, Ghaem Hospital, Faculty of Medicine, Mashhad University of Medical Sciencess, Mashhad, Iran
| | - Alireza Bari
- Hematology Department, Ghaem Hospital, Faculty of Medicine, Mashhad University of Medical Sciencess, Mashhad, Iran
| | - Seyedeh Tahereh Mohaddes
- Hematology Department, Ghaem Hospital, Faculty of Medicine, Mashhad University of Medical Sciencess, Mashhad, Iran
| | - Houshang Rafatpanah
- Inflammation and Inflammatory Diseases Research Center, Faculty of Medicine, Mashhad University of Medical sciences, Mashhad, Iran
| | - Ehsan Ghayour Karimani
- Molecular Diagnostic Unit, Research and Education Department, Razavi Hospitals, Mashhad, Iran
| | - Kobra Etminani
- Department of Medical Informatics, Molecular Medicine Department, Faculty of Medicine, Mashhad University of Medical sciences, Mashhad, Iran
| | - Amin Golabpour
- Department of Medical Informatics, Molecular Medicine Department, Faculty of Medicine, Mashhad University of Medical sciences, Mashhad, Iran
| | - Reza Torshizi
- Department of Modern Sciences and Technologies, Molecular Medicine Department, Faculty of Medicine, Mashhad University of Medical sciences, Mashhad, Iran
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Watanabe T. Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1-infected T cells. Blood 2017; 129:1071-1081. [PMID: 28115366 PMCID: PMC5374731 DOI: 10.1182/blood-2016-09-692574] [Citation(s) in RCA: 123] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 12/21/2016] [Indexed: 02/07/2023] Open
Abstract
Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) that develops through a multistep carcinogenesis process involving 5 or more genetic events. We provide a comprehensive overview of recently uncovered information on the molecular basis of leukemogenesis in ATL. Broadly, the landscape of genetic abnormalities in ATL that include alterations highly enriched in genes for T-cell receptor-NF-κB signaling such as PLCG1, PRKCB, and CARD11 and gain-of function mutations in CCR4 and CCR7 Conversely, the epigenetic landscape of ATL can be summarized as polycomb repressive complex 2 hyperactivation with genome-wide H3K27 me3 accumulation as the basis of the unique transcriptome of ATL cells. Expression of H3K27 methyltransferase enhancer of zeste 2 was shown to be induced by HTLV-1 Tax and NF-κB. Furthermore, provirus integration site analysis with high-throughput sequencing enabled the analysis of clonal composition and cell number of each clone in vivo, whereas multicolor flow cytometric analysis with CD7 and cell adhesion molecule 1 enabled the identification of HTLV-1-infected CD4+ T cells in vivo. Sorted immortalized but untransformed cells displayed epigenetic changes closely overlapping those observed in terminally transformed ATL cells, suggesting that epigenetic abnormalities are likely earlier events in leukemogenesis. These new findings broaden the scope of conceptualization of the molecular mechanisms of leukemogenesis, dissecting them into immortalization and clonal progression. These recent findings also open a new direction of drug development for ATL prevention and treatment because epigenetic marks can be reprogrammed. Mechanisms underlying initial immortalization and progressive accumulation of these abnormalities remain to be elucidated.
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Affiliation(s)
- Toshiki Watanabe
- Department of Advanced Medical Innovation, St. Marianna University Graduate School of Medicine, Kanagawa, Japan; and Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
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11
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Abstract
PURPOSE OF REVIEW To discuss current understanding of the mechanisms of human T-lymphotropic virus type-1 (HTLV-1) tumorigenesis and current and potential treatment strategies for adult T-cell leukaemia/lymphoma (ATL), an aggressive malignant disease of CD4 cells caused by HTLV-1. RECENT FINDINGS Treatment of the aggressive subtypes of ATL remains inadequate, with little improvement in overall survival in the 30 years since HTLV-1 was discovered. Detailed analysis of the clonal expansion of HTLV-1 has provided new insight into pathogenesis. Most HTLV-1-infected cells, including ATL, express CCR4 which can be targeted. Reports of antitumour effects with allogeneic bone marrow transplantation provide a rationale for novel immunotherapy approaches. Progress has been made in the indolent subtypes of ATL with the use of 'antiviral' therapies. SUMMARY ATL has poor prognosis. There is a major, urgent, unmet clinical need to identify HTLV carriers who will develop ATL to develop biomarkers of transforming disease and disease progression and to provide novel treatment approaches within the context of clinical trials. Several strategies now include putative or actual antiviral therapy. Potentially, the risk of ATL would be reduced by eliminating some or all infected clones. HTLV-1 infection, and hence ATL, can be prevented by antenatal HTLV-1 screening.
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12
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Kondo H, Soda M, Sawada N, Inoue M, Imaizumi Y, Miyazaki Y, Iwanaga M, Tanaka Y, Mizokami M, Tsugane S. Smoking is a risk factor for development of adult T-cell leukemia/lymphoma in Japanese human T-cell leukemia virus type-1 carriers. Cancer Causes Control 2016; 27:1059-1066. [PMID: 27412633 DOI: 10.1007/s10552-016-0784-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Accepted: 07/01/2016] [Indexed: 10/21/2022]
Abstract
BACKGROUND AND PURPOSE Adult T-cell leukemia/lymphoma (ATLL) is an aggressive hematological malignancy caused by human T-cell leukemia virus type-1 (HTLV-1); no effective methods have yet been identified to prevent development of ATLL in carriers of HTLV-1. This study investigated the association between cigarette smoking and the risk of ATLL development among Japanese carriers of HTLV-1. METHODS This study examined the association between smoking and development of ATLL in a cohort of 1,332 Japanese HTLV-1 carriers aged 40-69 years free of ATLL at baseline from two different HTLV-1-endemic areas of Japan. Cox proportional hazards models adjusted for sex, geographic area, age at baseline, and alcohol drinking were used to estimate the effect of cigarette smoking on ATLL development. RESULTS Between 1993 and 2012, 25 new ATLL cases were identified among these subjects. The overall crude incidence rate for ATLL was 1.08 per 1,000 person-years among HTLV-1 carriers and was higher among male carriers than among female carriers (2.21 vs. 0.74). The risk of ATLL development increased significantly with increasing numbers of cigarettes smoked per day (hazard ratio for every increment of 20 cigarettes, 2.03; 95 % confidence interval (CI) 1.13-3.66 overall, 2.07 (95 % CI 1.13-3.73) in male carriers). CONCLUSIONS Cigarette smoking may influence ATLL development among HTLV-1 carriers in Japan.
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Affiliation(s)
- Hisayoshi Kondo
- Biostatistics Section, Division of Scientific Data Registry, Atomic Bomb Disease Institute, Nagasaki University, Sakamoto 1-12-4, Nagasaki, 852-8523, Japan.
| | - Midori Soda
- Department of Epidemiology, Radiation Effects Research Foundation, Nagasaki, Japan
| | - Norie Sawada
- Epidemiology and Prevention Group, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
| | - Manami Inoue
- Epidemiology and Prevention Group, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
- Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | | | - Yasushi Miyazaki
- Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
| | - Masako Iwanaga
- Department of Frontier Life Science, Unit of Basic Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Masashi Mizokami
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Shoichiro Tsugane
- Epidemiology and Prevention Group, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
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13
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Abstract
Germline deletion of the p53 gene in mice gives rise to spontaneous thymic (T-cell) lymphomas. In this study, the p53 knockout mouse was employed as a model to study the mutational evolution of tumorigenesis. The clonality of the T-cell repertoire from p53 knockout and wild-type thymic cells was analyzed at various ages employing TCRβ sequencing. These data demonstrate that p53 knockout thymic lymphomas arose in an oligoclonal fashion, with tumors evolving dominant clones over time. Exon sequencing of tumor DNA revealed that all of the independently derived oligoclonal mouse tumors had a deletion in the Pten gene prior to the formation of the TCRβ rearrangement, produced early in development. This was followed in each independent clone of the thymic lymphoma by the amplification or overexpression of cyclin Ds and Cdk6. Alterations in the expression of Ikaros were common and blocked further development of CD-4/CD-8 T cells. While the frequency of point mutations in the genome of these lymphomas was one per megabase, there were a tremendous number of copy number variations producing the tumors' driver mutations. The initial inherited loss of p53 functions appeared to delineate an order of genetic alterations selected for during the evolution of these thymic lymphomas.
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14
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Daly JA, Mortlock SA, Taylor RM, Williamson P. Cluster Analysis of Tumor Suppressor Genes in Canine Leukocytes Identifies Activation State. Bioinform Biol Insights 2015; 9:59-67. [PMID: 27478369 PMCID: PMC4955975 DOI: 10.4137/bbi.s30523] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Revised: 05/23/2016] [Accepted: 05/29/2016] [Indexed: 02/07/2023] Open
Abstract
Cells of the immune system undergo activation and subsequent proliferation in the normal course of an immune response. Infrequently, the molecular and cellular events that underlie the mechanisms of proliferation are dysregulated and may lead to oncogenesis, leading to tumor formation. The most common forms of immunological cancers are lymphomas, which in dogs account for 8%–20% of all cancers, affecting up to 1.2% of the dog population. Key genes involved in negatively regulating proliferation of lymphocytes include a group classified as tumor suppressor genes (TSGs). These genes are also known to be associated with progression of lymphoma in humans, mice, and dogs and are potential candidates for pathological grading and diagnosis. The aim of the present study was to analyze TSG profiles in stimulated leukocytes from dogs to identify genes that discriminate an activated phenotype. A total of 554 TSGs and three gene set collections were analyzed from microarray data. Cluster analysis of three subsets of genes discriminated between stimulated and unstimulated cells. These included 20 most upregulated and downregulated TSGs, TSG in hallmark gene sets significantly enriched in active cells, and a selection of candidate TSGs, p15 (CDKN2B), p18 (CDKN2C), p19 (CDKN1A), p21 (CDKN2A), p27 (CDKN1B), and p53 (TP53) in the third set. Analysis of two subsets suggested that these genes or a subset of these genes may be used as a specialized PCR set for additional analysis.
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Affiliation(s)
- Julie-Anne Daly
- Faculty of Veterinary Science, The University of Sydney, Camperdown, NSW, Australia
| | - Sally-Anne Mortlock
- Faculty of Veterinary Science, The University of Sydney, Camperdown, NSW, Australia
| | - Rosanne M Taylor
- Faculty of Veterinary Science, The University of Sydney, Camperdown, NSW, Australia
| | - Peter Williamson
- Faculty of Veterinary Science, The University of Sydney, Camperdown, NSW, Australia
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15
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Yesudhas D, Gosu V, Anwar MA, Choi S. Multiple roles of toll-like receptor 4 in colorectal cancer. Front Immunol 2014; 5:334. [PMID: 25076949 PMCID: PMC4097957 DOI: 10.3389/fimmu.2014.00334] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2014] [Accepted: 07/01/2014] [Indexed: 12/14/2022] Open
Abstract
Toll-like receptor (TLR) signaling has been implicated in the inflammatory responses in intestinal epithelial cells (IECs). Such inflammatory signals mediate complex interactions between commensal bacteria and TLRs and are required for IEC proliferation, immune response, repair, and homeostasis. The upregulation of certain TLRs in colorectal cancer (CRC) tissues suggests that TLRs may play an essential role in the prognosis of chronic and inflammatory diseases that ultimately culminate in CRC. Here, we provide a comprehensive review of the literature on the involvement of the TLR pathway in the initiation, progression, and metastasis of CRC, as well as inherited genetic variation and epigenetic regulation. The differential expression of TLRs in epithelial cells has also been discussed. In particular, we emphasize the physiological role of TLR4 in CRC development and pathogenesis, and propose novel and promising approaches for CRC therapeutics with the aid of TLR ligands.
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Affiliation(s)
- Dhanusha Yesudhas
- Department of Molecular Science and Technology, Ajou University , Suwon , South Korea
| | - Vijayakumar Gosu
- Department of Molecular Science and Technology, Ajou University , Suwon , South Korea
| | - Muhammad Ayaz Anwar
- Department of Molecular Science and Technology, Ajou University , Suwon , South Korea
| | - Sangdun Choi
- Department of Molecular Science and Technology, Ajou University , Suwon , South Korea
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16
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Andersen MH. The targeting of immunosuppressive mechanisms in hematological malignancies. Leukemia 2014; 28:1784-92. [PMID: 24691076 DOI: 10.1038/leu.2014.108] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Revised: 02/20/2014] [Accepted: 03/13/2014] [Indexed: 12/20/2022]
Abstract
The adaptive immune system has the capacity to recognize and kill leukemic cells. However, immune tolerance mechanisms that normally protect healthy tissues from autoimmune effects prevent the development of effective antitumor immunity. Tumors use several different immunosuppressive mechanisms to evade otherwise effective T-cell responses. A growing number of immune evasion mechanisms have been characterized mainly in solid tumors. In hematological malignancies, less is known about how different immune escape mechanisms influence tumor immune evasion and the extent of their impact on ongoing immune responses. The present review highlights the potential role of three well-defined immunosuppressive mechanisms in hematological malignancies: (i) inhibitory T-cell pathways (especially programmed death ligand 1/programmed death 1 (PD-L1/PD-1)), (ii) regulatory immune cells, and (iii) metabolic enzymes such as indoeamine-2,3-dioxygenase (IDO). The possible therapeutic targeting of these pathways is also discussed. Exciting new strategies that might affect future antileukemia immunotherapy include monoclonal antibodies that block inhibitory T-cell pathways (PD-1/PD-L1) and the prevention of tryptophan depletion by IDO inhibitors. Furthermore, the clinical effect of several chemotherapeutic drugs may arise from the targeting of immunosuppressive cells. Evidence for a new feedback mechanism to suppress the function of regulatory immune cells was recently provided by the identification and characterization of spontaneous cytotoxic T lymphocyte (CTL) responses against regulatory immune cells. Such specific CTLs may be immensely useful in anticancer immunotherapy (for example, by anticancer vaccination). The targeting of one or more immunosuppressive pathways may be especially interesting in combination with antileukemic immunotherapy in cases in which immunosuppressive mechanisms antagonize the desired effects of the therapy.
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Affiliation(s)
- M H Andersen
- Department of Hematology, Center for Cancer Immune Therapy (CCIT), Copenhagen University Hospital, Herlev, Denmark
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17
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Zhi H, Zahoor MA, Shudofsky AMD, Giam CZ. KSHV vCyclin counters the senescence/G1 arrest response triggered by NF-κB hyperactivation. Oncogene 2014; 34:496-505. [PMID: 24469036 PMCID: PMC4112183 DOI: 10.1038/onc.2013.567] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Revised: 11/20/2013] [Accepted: 11/29/2013] [Indexed: 12/19/2022]
Abstract
Many oncogenic viruses activate NF-κB as a part of their replicative cycles. We have shown recently that persistent and potentially oncogenic activation of NF-κB by the human T-lymphotropic virus 1 (HTLV-1) oncoprotein Tax immediately triggers a host senescence response mediated by cyclin-dependent kinase inhibitors: p21CIP1/WAF1 (p21) and p27Kip1 (p27) Here we demonstrate that RelA/NF-κB activation by Kaposi sarcoma herpesvirus (KSHV) latency protein vFLIP also leads to p21/p27 up-regulation and G1 cell cycle arrest. Remarkably, KSHV vCyclin, another latency protein co-expressed with vFLIP from a bicistronic latency-specific mRNA, was found to prevent the senescence and G1 arrest induced by HTLV-1 Tax and vFLIP respectively. This is due to the known ability of vCyclin/CDK6 complex to resist p21 and p27 inhibition and cause p27 degradation23. In KSHV-transformed BCBL-1 cells, sustained vFLIP expression with shRNA-mediated vCyclin depletion resulted in G1 arrest. The functional interdependence of vFLIP and vCyclin explains why they are co-translated from the same viral mRNA. Importantly, deregulation of the G1 cyclin-dependent kinase can facilitate chronic IKK/NF-κB activation.
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Affiliation(s)
- H Zhi
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - M A Zahoor
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - A M D Shudofsky
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - C-Z Giam
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
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18
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Harnessing PD-L1-specific cytotoxic T cells for anti-leukemia immunotherapy to defeat mechanisms of immune escape mediated by the PD-1 pathway. Leukemia 2013; 28:236-8. [DOI: 10.1038/leu.2013.261] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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19
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Yoshida N, Nishikori M, Izumi T, Imaizumi Y, Sawayama Y, Niino D, Tashima M, Hoshi S, Ohshima K, Shimoyama M, Seto M, Tsukasaki K. Primary peripheral T-cell lymphoma, not otherwise specified of the thyroid with autoimmune thyroiditis. Br J Haematol 2013; 161:214-23. [PMID: 23432459 DOI: 10.1111/bjh.12255] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2012] [Accepted: 01/11/2013] [Indexed: 01/08/2023]
Abstract
Primary peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) of the thyroid is an extremely rare neoplasm. Six cases of primary PTCL-NOS of the thyroid were analysed for clinicopathological features and genomic alteration patterns using oligo-array comparative genomic hybridization. All patients had a diffusely enlarged thyroid and three cases showed leukaemic manifestation. Five of the six cases had anti-thyroid antibodies and the remaining case showed hypothyroidism, suggesting that all cases had autoimmune thyroiditis. Except for one early relapsed case, the remaining five patients are alive and three of these five individuals have survived for 70 months or more. Interestingly, two cases showed spontaneous regressions after partial thyroid biopsy without any therapy. Leukaemic manifestation disappeared after irradiation of the thyroid mass in another two cases. The tumour cells were positive for CD3, CD4 and CXCR3 in all cases, suggesting that the tumour cells are of a type 1 helper T-cell origin. All six cases showed genomic alterations that were different from those previously reported for PTCL-NOS. The loss of 6q24·2 was characteristic and was detected in four of the six cases. These results suggest that primary PTCL-NOS of the thyroid arising from autoimmune thyroiditis is a distinct disease entity among heterogeneous PTCL-NOS.
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Affiliation(s)
- Noriaki Yoshida
- Division of Molecular Medicine, Aichi Cancer Centre Research Institute, Nagoya, Japan
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20
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Markedly additive antitumor activity with the combination of a selective survivin suppressant YM155 and alemtuzumab in adult T-cell leukemia. Blood 2013; 121:2029-37. [PMID: 23321252 DOI: 10.1182/blood-2012-05-427773] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4(+)CD25(+) lymphocytes caused by human T-cell lymphotropic virus type 1. Currently, there is no accepted curative therapy for ATL. In gene expression profiling, the antiapoptotic protein survivin (BIRC5) demonstrated a striking increase in ATL, and its expression was increased in patient ATL cells resistant to the anti-CD52 monoclonal antibody alemtuzumab (Campath-1H). In this study, we investigated the antitumor activity of a small-molecule survivin suppressant YM155 alone and in combination with alemtuzumab in a murine model of human ATL (MET-1). Both YM155 alone and its combination with alemtuzumab demonstrated therapeutic efficacy by lowering serum soluble IL-2Rα (sIL-2Rα) levels (P < .001) and prolonged the survival of tumor-bearing mice (P < .0001). Moreover, the combination of YM155 with alemtuzumab demonstrated markedly additive antitumor activity by significantly lowering serum sIL-2Rα levels and improving the survival of leukemia-bearing mice compared with monotherapy with either YM155 (P < .001) or alemtuzumab (P < .05). More significantly, all mice that received the combination therapy survived and were tumor free >6 months after treatment. Our data support a clinical trial of the combination of YM155 with alemtuzumab in ATL. This trial was registered at www.clinicaltrials.gov as #NCT00061048.
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21
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Zane L, Yasunaga J, Mitagami Y, Yedavalli V, Tang SW, Chen CY, Ratner L, Lu X, Jeang KT. Wip1 and p53 contribute to HTLV-1 Tax-induced tumorigenesis. Retrovirology 2012; 9:114. [PMID: 23256545 PMCID: PMC3532233 DOI: 10.1186/1742-4690-9-114] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Accepted: 12/15/2012] [Indexed: 01/07/2023] Open
Abstract
Background Human T-cell Leukemia Virus type 1 (HTLV-1) infects 20 million individuals world-wide and causes Adult T-cell Leukemia/Lymphoma (ATLL), a highly aggressive T-cell cancer. ATLL is refractory to treatment with conventional chemotherapy and fewer than 10% of afflicted individuals survive more than 5 years after diagnosis. HTLV-1 encodes a viral oncoprotein, Tax, that functions in transforming virus-infected T-cells into leukemic cells. All ATLL cases are believed to have reduced p53 activity although only a minority of ATLLs have genetic mutations in their p53 gene. It has been suggested that p53 function is inactivated by the Tax protein. Results Using genetically altered mice, we report here that Tax expression does not achieve a functional equivalence of p53 inactivation as that seen with genetic mutation of p53 (i.e. a p53−/− genotype). Thus, we find statistically significant differences in tumorigenesis between Tax+p53+/+versus Tax+p53−/− mice. We also find a role contributed by the cellular Wip1 phosphatase protein in tumor formation in Tax transgenic mice. Notably, Tax+Wip1−/− mice show statistically significant reduced prevalence of tumorigenesis compared to Tax+Wip1+/+ counterparts. Conclusions Our findings provide new insights into contributions by p53 and Wip1 in the in vivo oncogenesis of Tax-induced tumors in mice.
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Affiliation(s)
- Linda Zane
- Molecular Virology Section, Laboratory of Molecular Microbiology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-0460, USA
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22
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Zane L, Sibon D, Capraro V, Galia P, Karam M, Delfau-Larue MH, Gilson E, Gessain A, Gout O, Hermine O, Mortreux F, Wattel E. HTLV-1 positive and negative T cells cloned from infected individuals display telomerase and telomere genes deregulation that predominate in activated but untransformed CD4+ T cells. Int J Cancer 2012; 131:821-33. [PMID: 21717459 DOI: 10.1002/ijc.26270] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2010] [Accepted: 05/12/2011] [Indexed: 01/02/2023]
Abstract
Untransformed HTLV-1 positive CD4(+) cells from infected individuals are selected for expressing tax and displaying morphological features consistent with telomere dysfunctions. We show that in resting HTLV-1 positive CD4(+) cells cloned from patients, hTERT expression parallels tax expression and cell cycling. Upon activation, these cells dramatically augment tax expression, whereas their increase in telomerase activity is about 20 times lower than that of their uninfected counterpart. Activated HTLV-1 positive CD4(+) but not uninfected CD4(+) or CD8(+) clones also repress the transcription of TRF1, TPP1, TANK1, POT1, DNA-PKc and Ku80. Both infected and uninfected lymphocytes from infected individuals shared common telomere gene deregulations toward a pattern consistent with premature senescence. ATLL cells displayed the highest telomerase activity (TA) whereas recovered a telomere gene transcriptome close to that of normal CD4(+) cells. In conclusion HTLV-1-dependent telomere modulations seem involved in clonal expansion, immunosuppression, tumor initiation and progression.
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Affiliation(s)
- Linda Zane
- Université de Lyon, Oncovirologie et Biothérapies, Centre Léon Bérard, Lyon, France
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23
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Xi Y, Watanabe S, Hino Y, Sakamoto C, Nakatsu Y, Okada S, Nakao M. Hmga1 is differentially expressed and mediates silencing of the CD4/CD8 loci in T cell lineages and leukemic cells. Cancer Sci 2012; 103:439-447. [PMID: 22106824 PMCID: PMC7713622 DOI: 10.1111/j.1349-7006.2011.02159.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2011] [Revised: 11/11/2011] [Accepted: 11/19/2011] [Indexed: 11/29/2022] Open
Abstract
High-mobility group A1 (Hmga1) protein is an architectural chromatin factor, and aberrant Hmga1 expression in mice causes hematopoietic malignancies with defects in cellular differentiation. However, the functional involvement of Hmga1 in hematopoietic development and leukemic cells remains to be elucidated. Using Hmga1-green fluorescent protein (GFP) knock-in mice that endogenously express an Hmga1-GFP fusion protein, we examined Hmga1 expression in undifferentiated and differentiated populations of hematopoietic cells. During early T cell development in the thymus, Hmga1 is highly expressed in CD4/CD8-double negative (DN) cells and is transiently downregulated in CD4/CD8-double positive (DP) cells. Consistently, Hmga1 directly binds to cis-regulatory elements in the CD4/CD8 loci and the heterochromatin foci in DN-stage cells, but not in DP cells. Interestingly, CD4/CD8 expression in DN-stage leukemic cells is induced by inhibition of Hmga1 binding to nuclear DNA or RNA interference-mediated Hmga1 knockdown. In addition, Hmga1-depleted leukemic T cells markedly diminish proliferation, with transcriptional activation of cyclin-dependent kinase inhibitor genes as a direct target of Hmga1. The data in the present study reveal a role of Hmga1 in transcriptional silencing in T cell lineages and leukemic cells.
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Affiliation(s)
- Yang Xi
- Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, and Global Center of Excellence Cell Fate Regulation Research and Education Unit, Kumamoto University, Kumamoto, Japan
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24
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Cotranscriptional Chromatin Remodeling by Small RNA Species: An HTLV-1 Perspective. LEUKEMIA RESEARCH AND TREATMENT 2012; 2012:984754. [PMID: 23213554 PMCID: PMC3504244 DOI: 10.1155/2012/984754] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2011] [Revised: 10/28/2011] [Accepted: 11/03/2011] [Indexed: 12/22/2022]
Abstract
Cell type specificity of human T cell leukemia virus 1 has been proposed as a possible reason for differential viral outcome in primary target cells versus secondary. Through chromatin remodeling, the HTLV-1 transactivator protein Tax interacts with cellular factors at the chromosomally integrated viral promoter to activate downstream genes and control viral transcription. RNA interference is the host innate defense mechanism mediated by short RNA species (siRNA or miRNA) that regulate gene expression. There exists a close collaborative functioning of cellular transcription factors with miRNA in order to regulate the expression of a number of eukaryotic genes including those involved in suppression of cell growth, induction of apoptosis, as well as repressing viral replication and propagation. In addition, it has been suggested that retroviral latency is influenced by chromatin alterations brought about by miRNA. Since Tax requires the assembly of transcriptional cofactors to carry out viral gene expression, there might be a close association between miRNA influencing chromatin alterations and Tax-mediated LTR activation. Herein we explore the possible interplay between HTLV-1 infection and miRNA pathways resulting in chromatin reorganization as one of the mechanisms determining HTLV-1 cell specificity and viral fate in different cell types.
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25
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Yamada Y, Kamihira S. Inactivation of tumor suppressor genes and the progression of adult T-cell leukemia-lymphoma. Leuk Lymphoma 2009; 46:1553-9. [PMID: 16236609 DOI: 10.1080/10428190500244217] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
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.
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Affiliation(s)
- Y Yamada
- Division of Laboratory Medicine, Department of Translational Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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26
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Nakagawa M, Nakagawa-Oshiro A, Karnan S, Tagawa H, Utsunomiya A, Nakamura S, Takeuchi I, Ohshima K, Seto M. Array comparative genomic hybridization analysis of PTCL-U reveals a distinct subgroup with genetic alterations similar to lymphoma-type adult T-cell leukemia/lymphoma. Clin Cancer Res 2009; 15:30-8. [PMID: 19118030 DOI: 10.1158/1078-0432.ccr-08-1808] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Peripheral T-cell lymphoma, unspecified (PTCL-U) comprises histopathologically and clinically heterogeneous groups. The purpose of this study was to identify subgroups with distinct genetic, histopathologic, and prognostic features. EXPERIMENTAL DESIGN We used array comparative genomic hybridization (CGH) for high-resolution analysis of 51 PTCL-U patients and the array data for examining possible correlations of histopathologic and clinical features. Moreover, we compared the genetic, histopathologic, and prognostic features of the PTCL-U cases with those of 59 cases of lymphoma-type adult T-cell leukemia/lymphoma (ATLL). RESULTS We identified 32 regions with frequent genomic imbalance, 1 region with high copy number gain at 14q32.2, and 1 region with homozygous loss at 9p21.3. Gains of 7p and 7q and loss of 9p21.3 showed a significant association with poor prognosis. PTCL-U cases with genomic imbalance showed distinct histopathologic and prognostic features compared with such cases without alteration and a marked genetic, histopathologic, and prognostic resemblance to lymphoma-type ATLL. CONCLUSIONS The array CGH enabled us to identify the frequently altered genomic regions with strong prognostic power among PTCL-U cases. A correlative analysis using the array CGH data disclosed a subgroup in PTCL-U with genomic alterations and with histopathologic and clinical relevance. In addition to histopathologic similarity, the strong genetic and prognostic resemblance between PTCL-U cases with genomic imbalance detected by array CGH and lymphoma-type ATLL seems to support the notion that the former may constitute a distinct PTCL-U subgroup.
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Affiliation(s)
- Masao Nakagawa
- Division of Molecular Medicine, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Japan
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27
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Gene expression profiling of ATL patients: compilation of disease-related genes and evidence for TCF4 involvement in BIRC5 gene expression and cell viability. Blood 2009; 113:4016-26. [PMID: 19131553 DOI: 10.1182/blood-2008-08-175901] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Adult T-cell leukemia/lymphoma (ATL) is an aggressive and fatal disease. We have examined 32 patients with smoldering, chronic, lymphoma and acute leukemia using Affymetrix HG-U133A2.0 arrays. Using the BRB array program, we identified genes differentially expressed in leukemia cells compared with normal lymphocytes. Several unique genes were identified that were overexpressed in leukemic cells, including TNFSF11, RGS13, MAFb, CSPG2, C/EBP-alpha, and TCF4; 200 of the most highly overexpressed ATL genes were analyzed by the Pathway Studio, version 4.0 program. ATL leukemia cells were characterized by an increase in genes linked to "central" genes CDC2/cyclin B1, SYK/LYN, proliferating cell nuclear antigen, and BIRC5. Because of its potential therapeutic importance, we focused our studies on the regulation and function of BIRC5, whose expression was increased in 13 of 14 leukemia samples. TCF4 reporter assays and transfection of DN-TCF4 demonstrated that TCF4 regulates BIRC5 gene expression. Functionally, transfection of ATL cells with BIRC5 shRNA decreased BIRC5 expression and cell viability 80%. Clinical treatment of ATL patients with Zenapax or bortezomib decreased BIRC5 expression and cell viability. These experiments represent the first direct experimental evidence that BIRC5 plays an important role in ATL cell viability and provides important insight into ATL genesis and potential targeted therapies.
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28
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Human T-cell leukemia virus type-1 antisense-encoded gene, Hbz, promotes T-lymphocyte proliferation. Blood 2008; 112:3788-97. [PMID: 18689544 DOI: 10.1182/blood-2008-04-154286] [Citation(s) in RCA: 157] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
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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29
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Kohno T, Yamada Y, Tawara M, Takasaki Y, Kamihira S, Tomonaga M, Matsuyama T. Inactivation of p14ARF as a key event for the progression of adult T cell leukemia/lymphoma. Leuk Res 2008; 31:1625-32. [PMID: 18246599 DOI: 10.1016/j.leukres.2006.12.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The INK4a/ARF locus encodes two different proteins, p16INK4a and p14ARF, which are crucial for two tumor suppressor pathways. We found that p14ARF mRNA expression was suppressed in 13 of 37 cases, among which 9 cases showed the inactivation of both of p14ARF and p16INK4a, and 4 cases showed the inactivation of p14ARF alone. The inactivation of p14ARF and the mutation of p53 are mutually exclusive. The patients with the p14ARF inactivation had shorter survival, similar to that of patients with the p53 mutation. These results indicate that the inactivation of p14ARF plays a key role in the progression of ATLL.
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Affiliation(s)
- Tomoko Kohno
- Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University, Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
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30
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Cheng J, Kydd AR, Nakase K, Noonan KM, Murakami A, Tao H, Dwyer M, Xu C, Zhu Q, Marasco WA. Negative regulation of the SH2-homology containing protein-tyrosine phosphatase-1 (SHP-1) P2 promoter by the HTLV-1 Tax oncoprotein. Blood 2007; 110:2110-20. [PMID: 17540846 PMCID: PMC1976352 DOI: 10.1182/blood-2006-11-058388] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Expression of SH(2)-homology-containing protein-tyrosine phosphatase-1 (SHP-1), a candidate tumor suppressor, is repressed in human T-cell leukemia virus type-1 (HTLV-1)-transformed lymphocyte cell lines, adult T-cell leukemia (ATL) cells, and in other hematologic malignancies. However, the mechanisms underlying regulation and repression of SHP-1 remain unclear. Herein, we cloned the putative full-length, hematopoietic cell-specific SHP-1 P2 promoter and identified the "core" promoter regions. HTLV-1 Tax profoundly represses P2 promoter activity and histone deacetylase-1 (HDAC1) potentiates such inhibition. NF-kappaB was implicated as both a rate-limiting factor for basal P2 promoter activity and important for Tax-induced promoter silencing (TIPS). Chromatin immunoprecipitation studies demonstrated that NF-kappaB dissociates from the SHP-1 P2 promoter following the binding of Tax and HDAC1. This is in agreement with coimmunoprecipitation studies where NF-kappaB competed with HDAC1 for association with Tax protein. We propose that in TIPS, Tax recruits HDAC1 to the SHP-1 P2 promoter and forms an inhibitory complex that results in deacetylation and dissociation of NF-kappaB from the promoter and attenuation of SHP-1 expression. TIPS provides a possible first step toward HTLV-1 leukemogenesis through its down-modulation of this key immediate early negative regulator of IL-2 signaling.
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MESH Headings
- Acetylation
- Adult
- Blotting, Western
- Chromatin Immunoprecipitation
- Gene Expression Regulation, Leukemic
- Gene Expression Regulation, Viral
- Gene Products, tax/physiology
- Gene Silencing
- Histone Deacetylase 1
- Histone Deacetylases/metabolism
- Human T-lymphotropic virus 1/genetics
- Humans
- Immunoprecipitation
- Interleukin-2/metabolism
- Leukemia-Lymphoma, Adult T-Cell/genetics
- Leukemia-Lymphoma, Adult T-Cell/metabolism
- Leukemia-Lymphoma, Adult T-Cell/virology
- Luciferases/metabolism
- Mutagenesis, Site-Directed
- NF-kappa B/genetics
- NF-kappa B/metabolism
- Promoter Regions, Genetic/genetics
- Protein Phosphatase 1
- Protein Tyrosine Phosphatase, Non-Receptor Type 1
- Protein Tyrosine Phosphatase, Non-Receptor Type 6/genetics
- Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism
- Transcriptional Activation
- Transfection
- Tumor Cells, Cultured
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Affiliation(s)
- Jihua Cheng
- Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA, USA
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31
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Ramos JC, Ruiz P, Ratner L, Reis IM, Brites C, Pedroso C, Byrne GE, Toomey NL, Andela V, Harhaj EW, Lossos IS, Harrington WJ. IRF-4 and c-Rel expression in antiviral-resistant adult T-cell leukemia/lymphoma. Blood 2007; 109:3060-8. [PMID: 17138822 PMCID: PMC1852214 DOI: 10.1182/blood-2006-07-036368] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2006] [Accepted: 11/11/2006] [Indexed: 01/08/2023] Open
Abstract
Adult T-cell leukemia/lymphoma (ATLL) is a generally fatal malignancy. Most ATLL patients fare poorly with conventional chemotherapy; however, antiviral therapy with zidovudine (AZT) and interferon alpha (IFN-alpha) has produced long-term clinical remissions. We studied primary ATLL tumors and identified molecular features linked to sensitivity and resistance to antiviral therapy. Enhanced expression of the proto-oncogene c-Rel was noted in 9 of 27 tumors. Resistant tumors exhibited c-Rel (6 of 10; 60%) more often than did sensitive variants (1 of 9; 11%). This finding was independent of the disease form. Elevated expression of the putative c-Rel target, interferon regulatory factor-4 (IRF-4), was observed in 10 (91%) of 11 nonresponders and in all tested patients with c-Rel+ tumors and occurred in the absence of the HTLV-1 oncoprotein Tax. In contrast, tumors in complete responders did not express c-Rel or IRF-4. Gene rearrangement studies demonstrated the persistence of circulating T-cell clones in long-term survivors maintained on antiviral therapy. The expression of nuclear c-Rel and IRF-4 occurs in the absence of Tax in primary ATLL and is associated with antiviral resistance. These molecular features may help guide treatment. AZT and IFN-alpha is a suppressive rather than a curative regimen, and patients in clinical remission should remain on maintenance therapy indefinitely.
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Affiliation(s)
- Juan Carlos Ramos
- Division of Hematology/Oncology, Department of Medicine, University of Miami Miller School of Medicine, FL 33136, USA
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32
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Arnold J, Yamamoto B, Li M, Phipps AJ, Younis I, Lairmore MD, Green PL. Enhancement of infectivity and persistence in vivo by HBZ, a natural antisense coded protein of HTLV-1. Blood 2006; 107:3976-82. [PMID: 16424388 PMCID: PMC1895283 DOI: 10.1182/blood-2005-11-4551] [Citation(s) in RCA: 152] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Natural antisense viral transcripts have been recognized in retroviruses, including human T-cell leukemia virus type 1 (HTLV-1), HIV-1, and feline immunodeficiency virus (FIV), and have been postulated to encode proteins important for the infection cycle and/or pathogenesis of the virus. The antisense strand of the HTLV-1 genome encodes HBZ, a novel nuclear basic region leucine zipper (b-ZIP) protein that in overexpression assays down-regulates Tax oncoprotein-induced viral transcription. Herein, we investigated the contribution of HBZ to HTLV-1-mediated immortalization of primary T lymphocytes in vitro and HTLV-1 infection in a rabbit animal model. HTLV-1 HBZ mutant viruses were generated and evaluated for viral gene expression, protein production, and immortalization capacity. Biologic properties of HBZ mutant viruses in vitro were indistinguishable from wild-type HTLV-1, providing the first direct evidence that HBZ is dispensable for viral replication and cellular immortalization. Rabbits inoculated with irradiated cells expressing HTLV-1 HBZ mutant viruses became persistently infected. However, these rabbits displayed a decreased antibody response to viral gene products and reduced proviral copies in peripheral blood mononuclear cells (PBMCs) as compared with wild-type HTLV-1-infected animals. Our findings indicated that HBZ was not required for in vitro cellular immortalization, but enhanced infectivity and persistence in inoculated rabbits. This study demonstrates that retroviruses use negative-strand-encoded proteins in the establishment of chronic viral infections.
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Affiliation(s)
- Joshua Arnold
- Department of Veterinary Biosciences, The Ohio State University, 1925 Coffey Road, Columbus, OH 43210, USA
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33
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Tabakin-Fix Y, Azran I, Schavinky-Khrapunsky Y, Levy O, Aboud M. Functional inactivation of p53 by human T-cell leukemia virus type 1 Tax protein: mechanisms and clinical implications. Carcinogenesis 2005; 27:673-81. [PMID: 16308315 DOI: 10.1093/carcin/bgi274] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Human T-cell leukemia virus type 1 (HTLV-I) has been implicated with the etiology of adult T-cell leukemia (ATL) and certain other clinical disorders. Although the leukemogenic mechanism of HTLV-1 is not fully understood yet, the viral Tax protein is widely regarded as a key factor in this mechanism. Tax can modulate the synthesis or function of many regulatory factors which control a wide range of normal and oncogenic cellular processes and therefore, it acts as a potent oncoprotein. In the last few years, special attention has been attracted to Tax interference with the transactivation function of p53, a tumor-suppressor protein that is involved in regulation of the cell-cycle and apoptosis and in maintaining the cellular genome integrity. p53 is mutated in approximately 60% of all human tumors. In contrast, mutant p53 is found in only small percentage of ATL patients. Nevertheless, p53 is inactive in the leukemic cells of most ATL patients and in most HTLV-1 transformed cells. By inactivating p53, Tax can immortalize the HTLV-1-infected cells and destabilize their genome. Consequently, such cells can progress toward the ultimate leukemic state by a stepwise accumulation of oncogenic mutations and other types of chromosomal aberrations. Furthermore, since p53 exists in most ATL patients in its wild-type form, its reactivation by therapeutic drugs might be an effective approach for ATL therapy. Several mechanisms have been proposed so far for Tax-induced p53 inactivation. Understanding the exact mechanism of this Tax effect is essential for designing effective means for this therapeutic approach. In this review article, we discuss the various mechanisms proposed for Tax interference with p53 functions and their clinical and therapeutic implications.
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Affiliation(s)
- Yulia Tabakin-Fix
- Department of Microbiology and Immunology, Cancer Research Center, Faculty of Health Sciences and Department of Life Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel
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34
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Takeuchi S, Matsushita M, Tsukasaki K, Takeuchi N, Tomonaga M, Komatsu N, Ikezoe T, Uehara Y, Koeffler HP. P53 codon 72 polymorphism is associated with disease progression in adult T-cell leukaemia/lymphoma. Br J Haematol 2005; 131:552-3. [PMID: 16281948 DOI: 10.1111/j.1365-2141.2005.05798.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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35
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Marriott SJ, Semmes OJ. Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response. Oncogene 2005; 24:5986-95. [PMID: 16155605 DOI: 10.1038/sj.onc.1208976] [Citation(s) in RCA: 150] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Human T-cell lymphotropic virus type I (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL), a rapidly progressing, clonal malignancy of CD4+ T lymphocytes. Fewer than one in 20 infected individuals typically develop ATL and the onset of this cancer occurs after decades of relatively symptom-free infection. Leukemic cells from ATL patients display extensive and varied forms of chromosomal abnormalities and this genomic instability is thought to be a major contributor to the development of ATL. HTLV-I encodes a regulatory protein, Tax, which is necessary and sufficient to transform cells and is therefore considered to be the viral oncoprotein. Tax interacts with numerous cellular proteins to reprogram cellular processes including, but not limited to, transcription, cell cycle regulation, DNA repair, and apoptosis. This review presents an overview of the impact of HTLV-I infection in general, and Tax expression in particular, on cell cycle progression and the repair of DNA damage. The contribution of these activities to genome instability and cellular transformation will be discussed.
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Affiliation(s)
- Susan J Marriott
- Baylor College of Medicine, Department of Molecular Virology and Microbiology, One Baylor Plaza, Houston, TX 77030, USA.
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36
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Abstract
The HTLV Tax protein is crucial for viral replication and for initiating malignant transformation leading to the development of adult T-cell leukemia. Tax has been shown to be oncogenic, since it transforms and immortalizes rodent fibroblasts and human T-lymphocytes. Through CREB, NF-kappaB and SRF pathways Tax transactivates cellular promoters including those of cytokines (IL-13, IL-15), cytokine receptors (IL-2Ralpha) and costimulatory surface receptors (OX40/OX40L) leading to upregulated protein expression and activated signaling cascades (e.g. Jak/STAT, PI3Kinase, JNK). Tax also stimulates cell growth by direct binding to cyclin-dependent kinase holenzymes and/or inactivating tumor suppressors (e.g. p53, DLG). Moreover, Tax silences cellular checkpoints, which guard against DNA structural damage and chromosomal missegregation, thereby favoring the manifestation of a mutator phenotype in cells.
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Affiliation(s)
- Ralph Grassmann
- Institut für Klinische und Molekulare Virologie, Universität Erlangen-Nürnberg, Schlossgarten 4, Germany.
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37
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Mone A, Puhalla S, Whitman S, Baiocchi RA, Cruz J, Vukosavljevic T, Banks A, Eisenbeis CF, Byrd JC, Caligiuri MA, Porcu P. Durable hematologic complete response and suppression of HTLV-1 viral load following alemtuzumab in zidovudine/IFN-{alpha}-refractory adult T-cell leukemia. Blood 2005; 106:3380-2. [PMID: 16076875 PMCID: PMC1895052 DOI: 10.1182/blood-2005-01-0335] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Adult T-cell leukemia (ATL) is a highly chemoresistant and usually fatal T-cell malignancy due to the human T-cell lymphotropic virus-1 (HTLV-1). After chemotherapy failure, antiretrovirals and interferon-alpha (IFN-alpha) produce brief responses followed by progression and death. More effective agents and new approaches to detect and treat minimal residual disease are needed. ATL cells express CD52, the target of the antibody alemtuzumab, which is active in a preclinical model of ATL and is cytotoxic for p53-deficient cells. A patient with refractory chronic ATL in transformation achieved longer than a 1-year complete hematologic response following 12 weeks of outpatient subcutaneous alemtuzumab. Persistent suppression of HTLV-1 viral load, even at recovery of T cells, after alemtuzumab and efficient in vitro complement-mediated cytotoxicity of primary ATL cells with mutated TP53 were observed. The unprecedented response and the profound suppression of HTLV-1 viral load observed in this patient suggest that further clinical investigation of alemtuzumab in ATL is warranted.
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Affiliation(s)
- Andrew Mone
- Division of Hematology-Oncology, Department of Internal Medicine, The Comprehensive Cancer Center, The Ohio State University, Columbus, 43210, USA
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38
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Mamane Y, Loignon M, Palmer J, Hernandez E, Césaire R, Alaoui-Jamali M, Hiscott J. Repression of DNA repair mechanisms in IRF-4-expressing and HTLV-I-infected T lymphocytes. J Interferon Cytokine Res 2005; 25:43-51. [PMID: 15684621 DOI: 10.1089/jir.2005.25.43] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Human T cell leukemia virus (HTLV) is the causative agent of adult T cell leukemia (ATL), an aggressive and fatal leukemia of CD4+ T lymphocytes in which interferon regulatory factor-4 (IRF-4) becomes constitutively expressed, concomitant with major alterations in host gene expression. When constitutively expressed in uninfected T lymphocytes, IRF-4 caused reduced expression of critical DNA repair genes, including Rad51, XRCC1, Ung1, RPA, and proliferative cell nuclear antigen (PCNA), a transcriptional phenotype with striking similarities to the profile observed in HTLV-infected T lymphocytes. Concomitant with the inhibition of gene expression and defects in the DNA repair pathways, increased sensitivity of T lymphocytes to various genotoxic stresses that challenged all major DNA repair pathways were detected. Together, these results support a role for IRF- 4 in the repression of DNA repair activity and an increase in the risk of mutations. IRF-4 may thus represent a previously unidentified endogenous transcriptional repressor of DNA repair mechanisms.
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Affiliation(s)
- Yaël Mamane
- Lady Davis Institute for Medical Research, McGill University, Montreal, Canada
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39
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Gatza ML, Chandhasin C, Ducu RI, Marriott SJ. Impact of transforming viruses on cellular mutagenesis, genome stability, and cellular transformation. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2005; 45:304-325. [PMID: 15645440 DOI: 10.1002/em.20088] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
It is estimated that 15% of all cancers are etiologically linked to viral infection. Specific cancers including adult T-cell leukemia, hepatocellular carcinoma, and uterine cervical cancer are associated with infection by human T-cell leukemia virus type I, hepatitis B virus, and high-risk human papilloma virus, respectively. In these cancers, genomic instability, a hallmark of multistep cancers, has been explicitly linked to the expression of oncoproteins encoded by these viruses. This review discusses mechanisms utilized by these viral oncoproteins, Tax, HBx, and E6/E7, to mediate genomic instability and cellular transformation.
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Affiliation(s)
- Michael L Gatza
- Interdepartmental Program in Cell and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
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40
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Takeuchi S, Takeuchi N, Tsukasaki K, Yang Y, Fermin AC, Tomonaga M, Miller CW, Seo H, Koeffler HP. Methylenetetrahydrofolate reductase genotype does not play a role in adult T-cell leukemia/lymphoma pathogenesis among human T-lymphotrophic virus type 1 carriers. Leuk Res 2004; 28:1039-41. [PMID: 15289015 DOI: 10.1016/j.leukres.2004.02.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2003] [Accepted: 02/09/2004] [Indexed: 10/26/2022]
Abstract
Human T-lymphotropic virus type 1 (HTLV-1) is associated with adult T-cell leukemia/lymphoma (ATL). However, the incidence of ATL is low among HTLV-1 carriers suggesting additional mechanisms are involved in the progression of the disease. A recent study found that polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene influence the susceptibility to malignant lymphoma. We have analyzed the MTHFR genotype in 81 HTLV-1 carriers and 87 ATL patients. No statistically significant associations were found between MTHFR genotype and development of ATL. These data suggest that genetic polymorphisms in the MTHFR locus do not play a role in ATL pathogenesis among HTLV-1 carriers.
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Affiliation(s)
- Seisho Takeuchi
- Department of Medicine, Kochi Medical School, Kochi University, Kochi, Japan
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41
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Abstract
T-cell non-Hodgkin's lymphoma (NHL) represents approximately 10% to 15% of all lymphomas in Western countries. Patients with T-cell NHL are often treated similarly to patients with intermediate grade B-cell NHL, although many reports have demonstrated lower overall survival rates in patients with T-cell NHL compared to patients with B-cell NHL. Updated classifications have recognized specific clinical and pathologic T-cell entities, such as peripheral T-cell lymphoma, not otherwise characterized, angioimmunoblastic lymphoma, systemic anaplastic T-cell lymphoma, adult T-cell leukemia/lymphoma, subcutaneous panniculitis-like T-cell lymphoma, hepatosplenic T-cell lymphoma, extranodal natural killer (NK)/T-cell lymphoma nasal type, and enteropathy-type intestinal T-cell lymphoma. Furthermore, these distinct T-cell NHL subtypes often warrant individualized diagnostic and therapeutic strategies, such as the associated cytophagic histiocytic panniculitis and hemophagocytic syndrome with subcutaneous panniculitis-like T-cell lymphoma, the chromosomal translocation t(2;5), leading to the nucleophosmin anaplastic lymphoma kinase fusion protein, viral pathogenesis of Epstein-Barr virus, human T-cell lymphotropic virus type-1 associated with extranodal NK/T-cell lymphoma nasal type and adult T-cell leukemia/lymphoma, respectively, and the role of radiation therapy in extranodal NK/T-cell lymphoma nasal type. Other active therapeutic agents in T-cell NHL include purine and pyrimidine antimetabolite agents (eg, nucleoside analogues and gemcitabine, respectively), denileukin diftitox, and antinucleoside or retinoic acid with interferon-alpha combination treatment. The exact role of transplantation in patients with T-cell NHL is unknown, but several case series have documented the feasibility of autologous and allogeneic transplant with reported long-term survival rates similar to transplanted B-cell NHL. Identification of relevant proto-oncogenes and tumor suppressor genes involved in the pathogenesis of T-cell NHL, such as the nucleophosmin anaplastic lymphoma kinase fusion protein, p53 and retinoblastoma gene, cyclin-dependent kinase inhibitors, histone deacetylation inhibitors, and infectious etiologies (eg, Epstein-Barr virus and Helicobacter pylori), in addition to their interplay with the various regulatory pathways of cell-cycle progression and apoptosis, represent potential candidates for molecular-based therapy. Prospective multi-institution clinical trials are critically important to determine the most effective treatment regimens that will continue to improve cure rates in these aggressive, yet treatable and often curable, diseases.
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Affiliation(s)
- Andrew M Evens
- Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine Medical School and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA
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42
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Olivera CJ, Bula CM, Bishop JE, Adorini L, Manchand P, Uskokovic MR, Norman AW. Characterization of five 19-nor-analogs of 1alpha,25(OH)2-Vitamin D3 with 20-cyclopropyl-modified side-chains: implications for ligand binding and calcemic properties. J Steroid Biochem Mol Biol 2004; 89-90:99-106. [PMID: 15225754 DOI: 10.1016/j.jsbmb.2004.04.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
The steroid hormone 1alpha,25(OH)(2)-Vitamin D(3) [1alpha,25(OH)(2)D(3)] exerts a wide variety of biological actions through one or more receptors/binding proteins. The nuclear Vitamin D receptor (VDR) when bound to its natural ligand, 1alpha,25(OH)(2)D(3), can stimulate transcription of a wide variety of genes. The synthesis of 1alpha,25(OH)(2)D(3) analogs allows the study of structure-function relationships between ligand and the VDR. 1alpha,25(OH)(2)D(3) is a conformationally flexible molecule; specifically the side-chain of the hormone can display a large variety of shapes for its receptor. Here, we describe and analyze the properties of 10 1alpha,25(OH)(2)D(3) analogs modified at the side-chain of which five lack carbon-19 (19-nor) but have a novel 20-cyclopropyl functionality. Analog NG [20,21-methylene-23-yne-26,27-F(6)-19-nor-1alpha,25(OH)(2)D(3)] possesses a respectable binding affinity for the VDR and exhibits a high transcriptional activity (EC(50) approximately 10pM), while retaining low induction of hypercalcemia in vivo in the mouse, making it a primary candidate for further analyses of its anti-proliferative and/or cell differentiating properties.
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43
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Franchini G, Fukumoto R, Fullen JR. T-Cell Control by Human T-Cell Leukemia/Lymphoma Virus Type 1. Int J Hematol 2003; 78:280-96. [PMID: 14686485 DOI: 10.1007/bf02983552] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) causes neoplastic transformation of human T-cells in a small number of infected individuals several years from infection. Collective evidence from in vitro studies indicates that several viral proteins act in concert to increase the responsiveness of T-cells to extracellular stimulation, modulate proapoptotic and antiapoptotic gene signals, enhance T-cell survival, and avoid immune recognition of the infected T-cells. The virus promotes T-cell proliferation by usurping several signaling pathways central to immune T-cell function, such as antigen stimulation and receptor-ligand interaction, suggesting that extracellular signals are important for HTLV-1 oncogenesis. Environmental factors such as chronic antigen stimulation may therefore be of importance, as also suggested by epidemiological data. Thus genetic and environmental factors together with the virus contribute to disease development. This review focuses on current knowledge of the mechanisms regulating HTLV-1 replication and the T-cell pathways that are usurped by viral proteins to induce and maintain clonal proliferation of infected T-cells. The relevance of these laboratory findings is related to clonal T-cell proliferation and adult T-cell leukemia/lymphoma development in vivo.
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Affiliation(s)
- Genoveffa Franchini
- Basic Research Laboratory, National Cancer Institute, Bethesda, Maryland 20892-5055, USA.
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44
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Gatza ML, Watt JC, Marriott SJ. Cellular transformation by the HTLV-I Tax protein, a jack-of-all-trades. Oncogene 2003; 22:5141-9. [PMID: 12910251 DOI: 10.1038/sj.onc.1206549] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The human T-cell leukemia virus type I (HTLV-I) is an oncogenic retrovirus that is responsible for adult T-cell leukemia and a neurological disease, HTLV-I-associated myelopathy/tropical spastic paraparesis. HTLV-I encodes an oncogenic protein, Tax, which affects a variety of cellular functions prompting it to be referred to as a jack-of-all trades. The ability of Tax to both transcriptionally regulate cellular gene expression and to functionally inactivate proteins involved in cell-cycle progression and DNA repair provide the basis for Tax-mediated transformation and leukemogenesis. This review will concentrate on the effects of Tax on the dysregulation of the G(1)/S and G(2)/M checkpoints as well as the suppression of DNA damage repair leading to cellular transformation.
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Affiliation(s)
- Michael L Gatza
- Interdepartmental Program in Cell and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
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45
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Takasaki Y, Yamada Y, Sugahara K, Hayashi T, Dateki N, Harasawa H, Kawabata S, Soda H, Ikeda S, Tomonaga M, Kamihira S. Interruption of p16 gene expression in adult T-cell leukaemia/lymphoma: clinical correlation. Br J Haematol 2003; 122:253-9. [PMID: 12846894 DOI: 10.1046/j.1365-2141.2003.04377.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
We previously reported that p16 gene deletion is involved in the development and progression of adult T-cell leukaemia/lymphoma (ATLL). To further investigate the significance of this gene in ATLL, we examined its expression status in 63 patients. Samples were analysed at DNA, mRNA and protein levels using real-time polymerase chain reaction (PCR), reverse transcription (RT)-coupled real-time PCR and Western blot respectively. Twenty-four patients (38.1%) were p16 gene negative, and they showed significantly shorter survival than p16-gene-positive patients. The expression of p16 mRNA in p16-gene-positive patients varied greatly, and cells from some patients showed up to several hundredfold higher expression than normal lymphocytes. Surprisingly, among 17 patients examined for p16 protein expression, all four patients with unusually high mRNA lacked p16 protein expression, indicating that p16 protein production in these patients was interrupted at the translational level. Moreover, these patients showed significantly shorter survival than p16-protein-positive patients. These results indicate that the presence of p16 gene and p16 mRNA do not necessarily indicate the production of p16 protein in ATLL, and that loss of p16 protein function is involved in progression of ATLL.
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Affiliation(s)
- Yumi Takasaki
- Department of Haematology, Molecular Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University School of Medicine, Nagasaki, Japan
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Takeuchi S, Takeuchi N, Tsukasaki K, Fermin AC, De Vas S, Seo H, Koeffler HP. Mutations in the retinoblastoma-related gene RB2/p130 in adult T-cell leukaemia/lymphoma. Leuk Lymphoma 2003; 44:699-701. [PMID: 12769348 DOI: 10.1080/1042819031000063480] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The retinoblastoma (Rb) family consists of the tumor suppressor Rb/p105 and related proteins p107 and Rb2/p130. Although the involvement of the RB/p105 gene in Adult T-cell leukaemia/lymphoma (ATL) has been studied, no mutational data is reported regarding the RB2/p130 gene in ATL. We screened for mutations of the RB2/p130 gene. Mutation was detected in 1 of 41 primary ATL sample. This is the first report describing mutation of the RB2/p130 gene in ATL, suggesting that RB2/p130 may be involved in the development of ATL, and may behave as a tumor suppressor gene in T lymphocytes.
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Affiliation(s)
- Seisho Takeuchi
- Department of Internal Medicine, Kochi Medical School, Okohcho, Nankoku, Kochi 783-8505, Japan.
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Foss FM, Aquino SL, Ferry JA. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 10-2003. A 72-year-old man with rapidly progressive leukemia, rash, and multiorgan failure. N Engl J Med 2003; 348:1267-75. [PMID: 12660391 DOI: 10.1056/nejmcpc030003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Affiliation(s)
- Francine M Foss
- Department of Hematology/Oncology, New England Medical Center, Massachusetts General Hospital and Harvard Medical School, Boston, USA
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Franchini G, Nicot C, Johnson JM. Seizing of T Cells by Human T-Cell Leukemia⧸Lymphoma Virus Type 1. Adv Cancer Res 2003; 89:69-132. [PMID: 14587871 DOI: 10.1016/s0065-230x(03)01003-0] [Citation(s) in RCA: 63] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) causes neoplastic transformation of human T-cells in a small number of infected individuals several years from infection. Several viral proteins act in concert to increase the responsiveness of T-cells to extracellular stimulation, modulate proapoptotic and antiapoptotic gene signals, enhance T-cell survival, and avoid immune recognition of the infected T-cells. The virus promotes T-cell proliferation by usurping several signaling pathways central to immune T-cell function. Viral proteins modulate the downstream effects of antigen stimulation and receptor-ligand interaction, suggesting that extracellular signals are important for HTLV-1 oncogenesis. Environmental factors such as chronic antigen stimulation are therefore important, as also suggested by epidemiological data. The ability of a given individual to respond to specific antigens is determined genetically. Thus, genetic and environmental factors, together with the virus, contribute to disease development. As in the case of other virus-associated cancers, HTLV-1-induced leukemia/lymphoma can be prevented by avoiding viral infection or by intervention during the asymptomatic phase with approaches able to interrupt the vicious cycle of virus-induced proliferation of a subset of T-cells. This review focuses on current knowledge of the mechanisms regulating HTLV-1 replication and the T-cell pathways that are usurped by viral proteins to induce and maintain clonal proliferation of infected T-cells in vitro. The relevance of these laboratory findings will be related to clonal T-cell proliferation and adult T-cell leukemia/lymphoma development in vivo.
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Affiliation(s)
- Genoveffa Franchini
- National Cancer Institute, Basic Research Laboratory, Bethesda, Maryland 20892, USA
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