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.

项目摘要成人T细胞白血病 - 淋巴瘤（ATL）是由人类T-引起的侵略性和致命恶性肿瘤淋巴病毒，1型（HTLV-1）。逆转录病毒主要是通过性传播或通过母乳喂养传播的。至少全球1000万人可能感染了HTLV-1。 ATL在美国不同地发生，主要影响来自加勒比海群岛的非洲后代，例如海地和牙买加，HTLV-1是内在的。 1和相关疾病代表了南佛罗里达州和纽约市的公共卫生问题，这是美国来自加勒比群岛及其后代的移民最多的地区。 HTLV的2-5％之间 1个感染者在其一生中发展了ATL。侵略性和最常见的ATL变体具有中位生存期为6-10个月，无法通过常规化疗来治愈。 HTLV-1感染是治疗挑战性，因为它在宿主T细胞中建立了潜伏期，该宿主经历了克隆扩张和遗传一生中的不稳定。 HTLV-1病毒启动子在组蛋白脱乙酰基酶的转录控制下（HDACS）在5'LTR上，由HTLV-1基本亮氨酸拉链因子（HBz），该因子（HBz）是由组成式转录的在病毒的3'末端的负面链。 HTLV-1启动子通过其自身的病毒蛋白进行反式激活，税收，将CREB和招募P300/CBP与5'LTR结合。鉴于这些调节机制，HDAC 广泛使用的抗肿瘤剂的抑制剂促进了潜伏期的HTLV-1激活。我们最近使用旧一代HDAC抑制剂丙戊酸（VPA）进行了一项试验试验。在ATL患者的维持治疗期间，与AZT/Interferon-α（IFNα）一起使用。我们假设VPA会重新激活HTLV-1，从而引起针对最小残留循环ATL细胞的免疫反应，该细胞通常在AZT/IFNα治疗期间持续存在。支持此概念，添加VPA导致治疗受试者中的HTLV-1临时负荷，并在一个受试者中诱导分子缓解。我们最近观察到 HDAC抑制剂（VPA和Belinostat）完全消除了HBZ并激活税收，然后凋亡。将AZT与Belinostat结合增强了ATL细胞死亡。基于这些概念，我们提出了一个试点审判使用Belinostat作为基于AZT的方案的巩固疗法。这项研究的目标是确定是否在人类受试者中将Belinostat添加到基于AZT的疗法放射线素ATL，以调查是否是否 Belinostat破坏HTLV-1潜伏期，从而引起体内细胞毒性T细胞反应，并阐明使用我们的临床前模型，ATL中Belinostat和HDAC抑制剂的分子基础。我们被中毒了这项高影响力的提案有望帮助推进ATL的治疗。

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.