Epigenetic Alterations and Targeted Therapies in North American ATLL

北美 ATLL 的表观遗传改变和靶向治疗

• 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
• 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

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。即使采用以下方法进行管理，3 年总体生存率也仅为 25% 最积极的化疗。目前尚无改变结果的靶向治疗。由此，改进了 迫切需要了解发病机制和新的治疗策略。我们和其他人已经表明 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， 预后较差。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突变明显增多，而控制表观遗传修饰的基因突变更少 TCR/NF-kappaB 信号通路中的突变比日本 ATLL 多。引人注目的是，出现的频率 我们的患者队列中的 EP300 突变 (20%) 约为日本队列 (5.7%) 的 4 倍。一 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 成熟 B 细胞和 T 细胞的许多功能方面。我们首次发现BCL6的表达 原代 ATLL 样品和 ATLL 细胞系中。有趣的是，NA-ATLL 细胞系明显比 J-ATLL细胞系对BCL6有抑制作用。其他实验表明，在 NA-ATLL 细胞中，BCL6 发挥着重要作用 在 NA-ATLL 细胞应对 S-期间升高的 DNA 复制应激时，它们发挥着至关重要的作用 细胞周期的阶段。这些细胞支持 S 期是 NA-ATLL 细胞的致命弱点的概念 但 J-ATLL 细胞对 PARP 抑制剂奥拉帕尼 (Olaparib) 非常敏感，但并非如此。这些发现支持我们的 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 用于治疗靶向。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 中。 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。