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.

项目摘要/摘要 成人T细胞白血病/淋巴瘤(ATLL)是一种恶性的CD4+T细胞疾病，它发生在人类的T细胞和 嗜淋巴病毒-1(HTLV-1)携带者。即使在管理的情况下，3年的总存活率也是非常低的25% 最激进的化疗。目前还不存在改变结果的靶向治疗。因此，改进了 迫切需要对发病机制的了解和新的治疗策略。我们和其他人已经展示了 在日本(J-ATLL)和北美(NA-ATLL)患者中诊断的ATLLS有很大的不同 临床行为，北美变种的特点是化疗难治性疾病和 预后更差。最近，我们对30例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显著增加，而表观遗传修饰基因突变明显减少 TCR/NF-kappaB信号通路的突变高于日本的ATLLS。令人惊讶的是， 我们患者队列中的EP300突变(20%)大约是日本队列中的4倍(5.7%)。一 在可被p300乙酰化的转录因子中，bcl6是一种转录抑制因子，它关键地控制 成熟的B和T细胞的许多功能方面。我们首次发现bcl6基因表达 在原代ATLL样本和ATLL细胞系中。有趣的是，NA-ATLL细胞系明显比 J-AT11细胞对BCL6的抑制作用。其他实验表明，在NA-ATLL细胞中，BCL6扮演着一种 在S期间，使NA-ATLL细胞在应对DNA复制压力升高时能够存活的关键作用- 细胞周期的阶段。支持S期是NA-ATLL细胞的阿喀琉斯之踵的概念，这些细胞 但J-ATLL细胞对PARP抑制剂奥拉帕里布并不是非常敏感。这些发现支持我们的 关于失调的表观遗传程序是自然生物学的中心特征的工作假说 减弱的p300活性与bcl6在S期程序中的独特作用相结合提供了一个新的机会 用于治疗靶向。为了检验这一假设，我们提出了以下三个具体目标。 目的1.阐明p300调控NA-AT11细胞染色质和基因表达的机制。 目的2.研究p300和bcl6在DNA复制程序和基因组稳定性调节中的作用 在纳塔尔。 目的3.确定PARPI敏感性的机制基础，设计针对S的治疗策略。 NA-ATLL的阶段脆弱性。