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; 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.

项目摘要/摘要 成人T细胞白血病/淋巴瘤（ATLL）是一种恶性CD4+ T细胞的疾病，在人T-中发展 淋巴病毒1（HTLV-1）载体。 3年的总生存率是糟糕的25％ 最具侵略性的化学疗法。目前没有改变结果的目标治疗。那是改进的 迫切需要了解发病机理和新颖的治疗策略。我们和其他人已经表明 在日语（J-ATLL）和北美（NA-ATLL）患者中被诊断出的ATLL的ATLL具有截然不同的 临床行为，其北美变体的特征是化学性侵犯性疾病的率较高和 预后较差。最近，我们在我们的30名患者中进行了第一个靶向外显子测序分析 中心并发现控制表观遗传修饰的基因突变明显更多，更少 与日本ATLL相比，TCR/NF-kappab信号通路中的突变。令人惊讶的是，频率 我们患者队列中的EP300突变（20％）大约是日本队列中看到的4次（5.7％）。一 可以通过p300乙酰化的转录因子是Bcl6，这是一种严重控制的转录复制器 成熟B和T细胞的许多功能方面。我们第一次发现Bcl6被表达 在主要的ATLL样品和ATLL细胞系中。有趣的是，Na-atll细胞系比 J-ATLL细胞系对BCl6抑制。其他实验表明，在Na-atll细胞中，Bcl6扮演 当Na-atll细胞应对s-期间的DNA复制应力时，可以使Na-atll细胞的存活率的重要作用 支持S期是Na-Atll细胞的致命弱点的概念，这些细胞 但是，J-ATLL细胞对PARP抑制剂Olaparib完全敏感。这些发现支持我们 工作假设，表观遗传程序失调是Na-Atll生物学的主要特征，并且 衰减的P300活动与BCl6在S相计划中的独特作用相结合提供了新的机会 用于治疗靶向。提出了以下三个特定目的来检验这一假设。 AIM 1。阐明P300调节Na-Atll中染色质和基因表达的机制。 AIM 2。将P300和BCL6的作用描述为DNA复制程序和基因组稳定性的调节剂 在na-atll中。 目标3。确定parpi敏感性和设计理论策略的机械基础，以针对S- Na-atll的相位脆弱性。