权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Epigenetic Targeting of Afro-Caribbean Variant of HTLV-1 Related Adult T-cell Leukemia-lymphoma

HTLV-1 相关成人 T 细胞白血病-淋巴瘤的非洲-加勒比变体的表观遗传靶向

基本信息

批准号：
10312764
负责人：
Juan Carlos Ramos
金额：
$ 33.01万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10312764
关键词：
Acetylation Adult T-Cell Leukemia/Lymphoma Affect African African Caribbean Antineoplastic Agents Apoptosis Area Autoimmune Binding Biological Breast Feeding CREB1 gene Cell Death Cells ChIP-seq Chromatin Clinical Clinical Trials Clonal Expansion Clone Cells Consolidation Therapy Cytotoxic T-Lymphocytes Data Dermatologic Development Disease Disease remission Dose EP300 gene Epigenetic Process Florida Generations Genetic Haiti Histone Deacetylase Histone Deacetylase Inhibitor Human Human T-Cell Leukemia Viruses Human T-lymphotropic virus 1 Immigrant Immune response Individual Infection Inflammatory Interferon-alpha Interferons Jamaica Long Terminal Repeats Lymphoma cell Maintenance Therapy Malignant Neoplasms Molecular New York City Paresis Pathogenicity Patients Persons Play Population Population Group Pre-Clinical Model Prognosis Proteins Proviruses Public Health RNA Regimen Regulation Residual state Retroviridae Reverse Transcriptase Inhibitors Role Sexual Transmission T cell clonality T cell response T-Cell Lymphoma T-Lymphocyte Taxes Transcriptional Regulation United States Valproic Acid Variant Vertebral column Viral Viral Proteins Virus West Indies Zidovudine bZIP Domain base cancer type cell killing chemotherapy drug maintenance genome-wide human subject immunogenic in vivo neglect nervous system disorder novel novel drug class novel therapeutic intervention pilot trial promoter recruit response tax Gene Products therapeutic target

项目摘要

PROJECT SUMMARY Adult T-cell leukemia-lymphoma (ATL) is an aggressive and fatal malignancy caused by the human T- lymphotropic virus, type 1 (HTLV-1). The retrovirus is primarily transmitted sexually or via breastfeeding. At least 10 million people worldwide may be infected with HTLV-1. ATL occurs disparately in the U.S. affecting mainly African descendants from the Caribbean islands, such as Haiti and Jamaica, where HTLV-1 is endemic. HTLV- 1 and related diseases represent a public health concern in South Florida and New York City, which are the U.S. areas most populated by immigrants from the Caribbean islands, and their descendants. Between 2-5% of HTLV- 1 infected individuals develop ATL during their lifetime. The aggressive and most common ATL variants have a median survival of 6-10 months, and cannot be cured by conventional chemotherapy. HTLV-1 infection is challenging to treat because it establishes latency in host T-cells, which undergo clonal expansion and genetic instability over a lifetime. The HTLV-1 provirus promoter is under transcriptional control of histone deacetylases (HDACs) at the 5' LTR, and by HTLV-1 basic leucine zipper factor (HBZ), which is constitutively transcribed from the negative strand at the 3' end of the provirus. The HTLV-1 promoter is transactivated by its own viral protein, Tax, which binds CREB and recruits p300/CBP to the 5' LTR. Given these mechanisms of regulation, HDAC inhibitors, which are widely used anti-neoplastic agents, promote the activation of HTLV-1 from latency. We recently conducted a pilot trial using the old generation HDAC inhibitor valproic acid (VPA) combined sequentially with AZT/interferon-α (IFNα) during maintenance therapy in patients with ATL. We hypothesized that VPA would reactivate HTLV-1 thus provoking an immune response against minimal residual circulating ATL cells, which normally persist during AZT/IFNα therapy alone. Supporting this notion, adding VPA resulted in reduction of HTLV-1 proviral load in treated subjects, and induced molecular remission in one subject. We recently observed that HDAC inhibitors (VPA, and belinostat) completely abrogate HBZ and activate Tax followed by apoptosis. Combining AZT with belinostat augmented ATL cell death. Based on these concepts, we proposed a pilot trial using belinostat as consolidation therapy with AZT-based regimen. The objectives of this study are to determine whether adding belinostat to AZT-based therapy eradicates ATL in human subjects, to investigate whether belinostat disrupts HTLV-1 latency thus provoking a cytotoxic T-cell response in vivo, and to elucidate the molecular basis of belinostat and HDAC inhibitors in ATL using our pre-clinical models. We are poised to carry out this high-impact proposal that promises to help advance the treatment of ATL.

项目总结成人T细胞白血病淋巴瘤(ATL)是由人类T细胞淋巴瘤引起的一种侵袭性和致命性的恶性肿瘤。嗜淋巴病毒1型(HTLV-1)。逆转录病毒主要通过性传播或通过母乳喂养传播。至少全球可能有1000万人感染HTLV-1。ATL在美国的发生情况不同，主要影响来自加勒比海岛屿的非洲后裔，如海地和牙买加，在那里HTLV-1是地方病。HTLV- 1及相关疾病是美国佛罗里达州南部和纽约市的公共卫生问题。来自加勒比海岛屿的移民及其后代居多的地区。HTLV的2%-5%- 1名感染者在其一生中发展为ATL。最常见的侵略性ATL变体具有中位生存期为6-10个月，不能通过常规化疗治愈。HTLV-1感染是治疗具有挑战性，因为它在宿主T细胞中建立潜伏期，宿主T细胞经历克隆扩增和遗传一生的不稳定。HTLV-1前病毒启动子受组蛋白脱乙酰酶的转录控制 (HDACs)和HTLV-1碱性亮氨酸拉链因子(HBZ)，后者是从前病毒3‘端的负链。HTLV-1启动子被自身的病毒蛋白反式激活， Tax，对CREB具有约束力，并将p300/CBP招募到5‘LTR。鉴于这些监管机制，人类发展援助委员会抑制剂是广泛使用的抗肿瘤药物，从潜伏期促进HTLV-1的激活。我们最近进行了一项中试，使用老一代HDAC抑制剂丙戊酸(VPA)顺序联合使用 AZT/干扰素-α(干扰素α)维持治疗在急性淋巴细胞白血病中的应用我们假设VPA会重新激活HTLV-1从而激发对最小残留循环ATL细胞的免疫反应，通常在α治疗期间持续存在。支持这一概念，添加VPA会导致 HTLV-1前病毒载量在治疗对象中，并在一名对象诱导分子缓解。我们最近观察到 HDAC抑制剂(VPA和贝力诺)完全消除HBZ，激活TAX，继而发生细胞凋亡。联合应用AZT和贝力诺能增加ATL细胞的死亡。基于这些概念，我们提出了试点试验以倍力诺为基础的AZT方案作为巩固治疗方案。这项研究的目标是确定在以AZT为基础的治疗中加入贝力诺是否能根除人类的ATL，以调查是否 Belinostat阻断HTLV-1潜伏期从而在体内引发细胞毒性T细胞反应，并阐明使用我们的临床前模型研究贝力诺和HDAC抑制剂在ATL中的分子基础。我们已经准备好携带提出了这项承诺有助于推进ATL治疗的高影响力提案。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CADM1 is essential for KSHV-encoded vGPCR-and vFLIP-mediated chronic NF-κB activation.

DOI：
10.1371/journal.ppat.1006968
发表时间：
2018-04
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Hunte R;Alonso P;Thomas R;Bazile CA;Ramos JC;van der Weyden L;Dominguez-Bendala J;Khan WN;Shembade N
通讯作者：
Shembade N

Updates in lymph node and skin pathology of adult T-cell leukemia/lymphoma, biomarkers, and beyond.

DOI：
10.1053/j.semdp.2019.12.006
发表时间：
2020-01
期刊：
Seminars in diagnostic pathology
影响因子：
2.3
作者：
Adkins BD;Ramos JC;Bliss-Moreau M;Gru AA
通讯作者：
Gru AA

Real-World Data on Adult T-Cell Leukemia/Lymphoma in Latin America: A Study From the Grupo de Estudio Latinoamericano de Linfoproliferativos.

DOI：
10.1200/go.21.00084
发表时间：
2021-07
期刊：
JCO global oncology
影响因子：
4.5
作者：
Malpica L;Enriquez DJ;Castro DA;Peña C;Idrobo H;Fiad L;Prates M;Otero V;Biglione M;Altamirano M;Sandival-Ampuero G;Aviles-Perez U;Meza K;Aguirre-Martinez L;Cristaldo N;Maradei JL;Guanchiale L;Soto P;Viñuela JL;Cabrera ME;Paredes SR;Riva E;Di Stefano M;Noboa A;Choque JA;Candelaria M;Von Glasenapp A;Valvert F;Torres-Viera MA;Castillo JJ;Ramos JC;Villela L;Beltran BE
通讯作者：
Beltran BE

Switching and loss of cellular cytokine producing capacity characterize in vivo viral infection and malignant transformation in human T- lymphotropic virus type 1 infection.