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：
9513500
负责人：
CHRISTOPHE P NICOT
金额：
$ 34.71万
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/9513500
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 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.

项目摘要/摘要人类T细胞白血病病毒I型（HTLV-i）是一种感染和转化人CD4的Onco-Retrovirus T细胞体外和体内。 HTLV-I是成人T细胞白血病/淋巴瘤（ATLL）的病因侵略性和致命的血液学疾病。该病毒是通过性接触传播的，通过母乳喂养污染了血液和母亲，并在全球拥有20-300万人。 HTLV-I介导的T细胞转化是由多步致癌过程引起的，其中病毒诱导慢性T细胞增殖，导致遗传缺陷的积累和失调的细胞生长。还没有完全了解HTLV-I如何产生ATLL，但是该病毒阻止了凋亡网络并花费了感染细胞的增殖能力。 HTLV-I在体外和之后使原代人T细胞感染并永生几个月，这些细胞获得了在没有白介素2的情况下生长的能力，称为转型。我们先前证明了病毒致癌税可以重新激活端粒酶表达，在体外和体内长期扩散的HTLV-I转化细胞所需的事件。这应用将调查与失调的端粒酶活性相关的分子事件及其在 HTLV-1转换过程。由于端粒酶重新激活代表了人类的核心步骤之一癌变，这项研究的结果将超出病毒肿瘤发生的广泛应用。