Epigenetic Alterations and Targeted Therapies in North American ATLL

北美 ATLL 的表观遗传改变和靶向治疗

基本信息

批准号：
10660553
负责人：
Bihui Hilda Ye
金额：
$ 55.24万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10660553
关键词：
Acetylation Acetyltransferase Adult T-Cell Leukemia/Lymphoma American Attenuated B-Lymphocytes BCL6 gene Behavior Biological Assay Biology Breast Cancer Cell CD4 Positive T Lymphocytes Caribbean region Cell Cycle Cell Line Cells Chemoresistance Chromatin Clinical Clinical Management Clonal Expansion DNA Damage DNA Methylation DNA Repair DNA biosynthesis DNA replication fork Decitabine Defect Diagnosis Disease Drug Targeting E1A-associated p300 protein EP300 gene Enhancers Epigenetic Process Event Exons Frequencies Gene Expression Genes Genetic Genome Stability Genomic Instability Genomics Hematopoiesis Histones Hospitals Human T-lymphotropic virus 1 Immunoglobulin Genes Japan Japanese Latin American Lymphoma cell Lysine Malignant - descriptor Malignant Neoplasms Mature B-Lymphocyte Mature T-Lymphocyte Modification Molecular Mutate Mutation NF-kappa B NOTCH1 gene North America Outcome Pathogenesis Pathogenicity Pathway interactions Patients Pattern Phenotype Physiological Play Poly(ADP-ribose) Polymerase Inhibitor Pre-Clinical Model Process Prognosis Refractory Disease Reporting Role S phase Sampling Signal Pathway T-Lymphocyte TP53 gene Testing Therapeutic Time Transcription Repressor Variant c-myc Genes chemotherapy cohort coping cytotoxicity design efficacy evaluation epigenetic regulation experience experimental study genome-wide homologous recombination improved in vitro activity novel novel therapeutic intervention novel therapeutics pre-clinical programs replication stress response targeted agent targeted sequencing targeted treatment therapeutic target transcription factor treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT Adult T-cell leukemia/lymphoma (ATLL) is a disease of malignant CD4+ T cells that develops in human T- lymphotropic virus-1 (HTLV-1) carriers. The 3-yr overall survival is an abysmal 25% even when managed with the most aggressive chemotherapy. No outcome-changing targeted treatment currently exists. Thus, improved understanding of pathogenesis and novel therapeutic strategies are urgently needed. We and others have shown that ATLLs diagnosed in the Japanese (J-ATLL) and North American (NA-ATLL) patients have very different clinical behavior, with the North American variant characterized by a higher rate of chemo-refractory disease and worse prognosis. Recently, we performed the first targeted exon sequencing analysis in 30 patients seen at our center and discovered significantly more mutations in genes controlling epigenetic modifications and fewer mutations in the TCR/NF-kappaB signaling pathways than the Japanese ATLLs. Strikingly, the frequency of EP300 mutations in our patient cohort (20%) was about 4 times that seen in the Japanese cohort (5.7%). One of the transcription factors that can be acetylated by p300 is BCL6, a transcription repressor that critically controls many functional aspects of mature B and T cells. We have discovered for the first time that BCL6 is expressed in primary ATLL samples and ATLL cell lines. Interestingly, NA-ATLL cell lines are notably more sensitive than J-ATLL cell lines to BCL6 inhibition. Additional experiments suggest that in NA-ATLL cells, BCL6 plays an essential role enabling survival of NA-ATLL cells as they cope with elevated DNA replication stress during S- phase of the cell cycle. Supporting the concept that the S-phase is an Achilles’ heel of NA-ATLL cells, these cells but not the J-ATLL cells are exquisitely sensitive to a PARP inhibitor, Olaparib. These findings support our working hypothesis that dysregulated epigenetic program is a central feature of NA-ATLL biology and that attenuated p300 activity combined with a unique role of BCL6 in S-phase programs provides a novel opportunity for therapeutic targeting. The following three specific aims are proposed to test this hypothesis. Aim 1. Elucidate the mechanisms by which p300 regulates chromatin and gene expression in NA-ATLL. Aim 2. Characterize the roles of p300 and BCL6 as regulators of DNA replication program and genome stability in NA-ATLL. Aim 3. Determine the mechanistic basis of PARPi sensitivity and design therapeutic strategies to target the S- phase vulnerabilities of NA-ATLL.

项目概要/摘要成人 T 细胞白血病/淋巴瘤 (ATLL) 是一种在人类 T 细胞中发生的恶性 CD4+ T 细胞疾病。嗜淋巴细胞病毒-1 (HTLV-1) 携带者即使采用治疗，3 年总生存率也仅为 25%。目前尚不存在最积极的化疗方案。我们和其他人已经表明，迫切需要了解发病机制和新的治疗策略。日本 (J-ATLL) 和北美 (NA-ATLL) 患者中诊断出的 ATLL 有很大不同临床行为，北美变体的特点是化疗难治性疾病的发生率较高，最近，我们对 30 名患者进行了首次靶向外显子测序分析。中心发现控制表观遗传修饰的基因发生更显着的突变，并且发现更少 TCR/NF-kappaB 信号通路的突变频率高于日本 ATLL。我们的患者队列中的 EP300 突变 (20%) 约为日本队列 (5.7%) 的 4 倍。可被 p300 乙酰化的转录因子中有 BCL6，它是一种转录抑制因子，关键控制我们首次发现 BCL6 表达于成熟 B 细胞和 T 细胞的许多功能方面。原代 ATLL 样品和 ATLL 细胞系中。 J-ATLL 细胞系对 BCL6 的抑制作用表明，在 NA-ATLL 细胞中，BCL6 发挥着重要作用。 NA-ATLL 细胞在应对 S-期间升高的 DNA 复制应激时发挥着至关重要的作用这些细胞支持细胞周期的 S 期是 NA-ATLL 细胞的致命弱点的概念。但 J-ATLL 细胞对 PARP 抑制剂 Olaparib 并非非常敏感。这些发现支持了我们的研究结果。工作假设：表观遗传程序失调是 NA-ATLL 生物学的一个核心特征，并且减弱的 p300 活性与 BCL6 在 S 期项目中的独特作用相结合提供了一个新的机会提出以下三个具体目标来检验这一假设。目标 1. 阐明 p300 在 NA-ATLL 中调节染色质和基因表达的机制。目标 2. 描述 p300 和 BCL6 作为 DNA 复制程序和基因组稳定性调节因子的作用在 NA-ATLL。目标 3. 确定 PARPi 敏感性的机制基础并设计针对 S-的治疗策略 NA-ATLL 的相位漏洞。