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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.

项目概要/摘要人类 T 细胞白血病病毒 I 型 (HTLV-I) 是一种致癌逆转录病毒，可感染并转化人类 CD4 T 细胞在体外和体内。 HTLV-I 是成人 T 细胞白血病/淋巴瘤 (ATLL) 的病原体，侵袭性且总是致命的血液疾病。该病毒通过性接触传播，母乳喂养会污染血液和母婴，全世界有 20-3000 万人存在这种情况。 HTLV-I 介导的 T 细胞转化源自多步骤致癌过程，其中病毒诱导慢性 T 细胞增殖，导致遗传缺陷积累和细胞生长失调。现在还没有完全理解 HTLV-I 如何产生 ATLL，但该病毒阻断了细胞凋亡网络并消耗了受感染细胞的增殖能力。 HTLV-I 在体外感染原代人类 T 细胞并使其永生化，之后几个月后，这些细胞获得了在没有白细胞介素 2 的情况下生长的能力，称为转变。我们之前证明病毒致癌税可以重新激活端粒酶表达，HTLV-I 转化细胞在体外和体内长期增殖所需的事件。这应用程序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。由于端粒酶重新激活代表了人类的核心步骤之一致癌作用，这项研究的结果将在病毒致癌作用之外具有广泛的应用。