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How HTLV-I Tax and HBZ control telomerase activity to induce adult T-cell leukemia

HTLV-I Tax 和 HBZ 如何控制端粒酶活性以诱导成人 T 细胞白血病

基本信息

批准号：
9304181
负责人：
CHRISTOPHE P NICOT
金额：
$ 34.72万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9304181
关键词：
Adult Precursor T Lymphoblastic Leukemia Adult T-Cell Leukemia/Lymphoma Affect Apoptotic Biology Blood Breast Feeding CD4 Positive T Lymphocytes Cells Child Chronic Development Disease Etiology Event FBXW7 gene Future Genetic Transcription Hela Cells Hematological Disease Human Human Activities Human T-Cell Leukemia Viruses In Vitro Individual Interferons Interleukin-2 JUN gene Laboratories Lymphoblastic Leukemia Maintenance Malignant Neoplasms Mediating Molecular Mothers Mutate Mutation NF-kappa B Oncogenic Oncoproteins Pathway interactions Patients Post-Transcriptional Regulation Process Publishing Regulation Regulatory Pathway Retroviridae Role Somatic Cell Spinal Cord Diseases T-Cell Proliferation T-Cell Transformation T-Lymphocyte TP53 gene Taxes Telomerase Telomere Shortening Therapeutic Transcriptional Activation Viral Virus Zidovudine base c-myc Genes cancer cell carcinogenesis cell growth cell transformation design in vitro Assay in vivo leukemia/lymphoma mutant neoplastic cell next generation sequencing novel overexpression promoter reconstitution senescence tax Gene Products therapeutic target tumorigenesis ubiquitin ligase

项目摘要

PROJECT SUMMARY/ABSTRACT The human T-cell leukemia virus type I (HTLV-I) is an onco-retrovirus that infects and transforms human CD4 T cells in vitro and in vivo. HTLV-I is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), an aggressive and invariably fatal hematological disease. The virus is transmitted through sexual contact, contaminated blood and mother-to-child by breastfeeding, and is present in 20-30 million people worldwide. HTLV-I-mediated T-cell transformation arises from a multi-step oncogenic process in which the virus induces chronic T-cell proliferation, resulting in accumulation of genetic defects and deregulated cell growth. It is not yet fully understood how HTLV-I engenders ATLL, but the virus blocks the apoptotic network and expends the proliferative capacity of infected cells. HTLV-I infects and immortalizes primary human T cells in vitro and, after several months, these cells acquire the ability to grow in the absence of interleukin-2, referred to as transformation. We previously demonstrated that the viral oncogenic Tax can reactivate telomerase expression, an event required for long-term proliferation of HTLV-I-transformed cells in vitro and in vivo. This application will investigate the molecular events associated with deregulated telomerase activity and its role in the HTLV-I transformation process. Since telomerase reactivation represents one of the central steps in human carcinogenesis, results from this study will have broad application beyond viral oncogenesis.

项目总结/摘要人类T细胞白血病病毒I型（HTLV-I）是一种感染并转化人类CD 4+细胞的肿瘤逆转录病毒体外和体内的T细胞。HTLV-I是成人T细胞白血病/淋巴瘤（ATLL）的病原体，侵袭性的、总是致命的血液病。病毒通过性接触传播，母乳喂养会污染血液和母婴，全球有2000万至3000万人感染。 HTLV-I介导的T细胞转化是由一个多步骤的致癌过程引起的，在该过程中，病毒诱导T细胞转化。慢性T细胞增殖，导致遗传缺陷的积累和细胞生长失调。目前尚不我们完全理解HTLV-I是如何产生ATLL的，但是这种病毒阻断了凋亡网络，感染细胞的增殖能力。HTLV-I在体外感染并永生化原代人T细胞，几个月后，这些细胞获得了在缺乏白细胞介素-2的情况下生长的能力，称为转型我们以前证明了病毒致癌Tax可以重新激活端粒酶，表达，这是HTLV-1转化细胞在体外和体内长期增殖所需的事件。这本申请将研究与端粒酶活性失调相关的分子事件及其在 HTLV-I转化过程。由于端粒酶再活化代表了人类肿瘤发生的中心步骤之一，致癌作用，这项研究的结果将有广泛的应用超出病毒致癌作用。