Elucidating transcriptional and epigenetic regulators of aggressive cutaneous T cell lymphoma

阐明侵袭性皮肤 T 细胞淋巴瘤的转录和表观遗传调节因子

基本信息

批准号：
10389198
负责人：
Calvin Yuen Yee Law
金额：
$ 4.2万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-15 至 2024-02-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10389198
关键词：
ATAC-seq Address Aggressive behavior Algorithms Bioinformatics Biological Assay Biological Models Blood CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Proliferation Cells Cellular Immunology Characteristics Chromatin Chronic Clinical Collection Communication Cutaneous Lymphoma Cutaneous T-cell lymphoma Data Development Disease Disease Outcome Down-Regulation Enhancers Epigenetic Process Exhibits Fellowship Foundations Functional disorder Future Genes Genetic Genetic Transcription Goals Homing Human Immunologics Indolent Joints Knock-out Knowledge Ligands Lymphoma Malignant Neoplasms Mediating Mentors Methods Modeling Molecular Non-Hodgkin&apos s Lymphoma Organ Outcome Pathogenesis Patients Phenotype Physicians Production Receptor Gene Receptor Signaling Research Role Sampling Scientist Signal Pathway Signal Transduction Skin System T-Cell Receptor T-Lymphocyte Techniques Training Transcriptional Regulation Tumor Suppressor Proteins Up-Regulation Visceral advanced disease base career cohort computerized tools cytokine differential expression digital disease heterogeneity disease phenotype epigenetic regulation epigenome exhaust exhaustion genetic signature genome sequencing genome-wide high throughput screening in vivo lead candidate lymph nodes multimodality mutant next generation novel therapeutic intervention programmed cell death ligand 1 programmed cell death protein 1 programs promoter rational design receptor skills standard of care therapeutic target transcription factor transcriptome sequencing transcriptomics tumor whole genome

项目摘要

Project Summary/Abstract Cutaneous T-cell lymphoma (CTCL) is an incurable non-Hodgkin lymphoma of skin homing T cells. Clinical outcomes of CTCL are highly heterogenous with some patients surviving <6 months and others >10 years in stage matched patients with advanced disease. The molecular mechanisms that drive heterogeneity of disease outcomes remain poorly understood. We have employed whole genome sequencing, RNA sequencing, and functional assays in a large cohort of primary patient samples to understand the genetic basis of CTCLs. We have identified deletion of PDCD1, a gene encoding the co-inhibitory receptor PD1, as a monogenic driver of CTCL disease aggression and phenotypes. Analysis of CTCLs in a multi-institutional cohort showed that PD1 deletion predicts a significantly worse overall survival in patients. This is recapitulated in our functional assays with primary patient samples where CTCLs with PD1 deletion displayed increased proliferation ex vivo. Notably, PD1 expressing CTCLs had increased expression of co-inhibitory receptors and gene signatures of T cell exhaustion, a dysfunctional state in T cells that limits effector functions. Interestingly, PD1 appears to drive a durable exhaustion phenotype that is retained by cells ex vivo even in the absence of ligand, suggesting that exhausted CTCLs have an epigenetic tumor suppressor program that is lost in PD1 deleted CTCLs. In addition, our preliminary RNA-seq data identified 60 transcription factors differentially expressed between PD1 expressing and deleted cohorts of CTCL, many but not all have been implicated in T cell exhaustion from studies with tumor models. Therefore, in this proposal, we aim to mechanistically dissect the epigenetic and transcriptional regulation of aggressive phenotypes in PD1-deleted CTCL samples. In Aim 1, we will identify whether transcription factors upregulated in PD1 expressing CTCLs are necessary or sufficient for in promoting CTCL exhaustion. In addition, we will also utilize primary patient samples to determine if the reversal of downregulation/upregulation of transcription factors in each CTCL cohort can reverse or increase exhaustion phenotypes. In Aim 2, we will elucidate the PD1 dependent epigenetic regulators in primary CTCLs We will combine epigenetic and transcriptomic data to identify differentially expressed transcription factors in each CTCL cohort in an unbiased way. My overall career goal is to become a successful, independent research scientist. The rigorous training plan proposed in this fellowship will allow me to achieve that goal by gaining research skills and knowledge in cellular immunology, cancer signaling pathways, and epigenetics. I will be mentored by Dr. Jaehyuk Choi, an expert physician-scientist in CTCL, and Dr. Deyu Fang, a world-renowned T cell biologist, who have devised a joint training plan to develop all necessary research skills, communication skills and promote my professional development. This fellowship will broaden our understanding of CTCL pathogenesis and T cell exhaustion, identify potential novel therapeutic strategies, and provide the necessary foundation for my future career as a research scientist.

项目概要/摘要皮肤T细胞淋巴瘤（CTCL）是一种无法治愈的皮肤归巢T细胞非霍奇金淋巴瘤。临床 CTCL 的结果具有高度异质性，一些患者存活 <6 个月，另一些患者存活 >10 年阶段匹配的晚期疾病患者。驱动疾病异质性的分子机制结果仍然知之甚少。我们采用了全基因组测序、RNA 测序和对大量主要患者样本进行功能测定，以了解 CTCL 的遗传基础。我们已经确定 PDCD1 的缺失（编码共抑制受体 PD1 的基因）是单基因驱动 CTCL 疾病侵袭和表型。对多机构队列中 CTCL 的分析表明，PD1 缺失预示着患者的总体生存率显着下降。这在我们的功能测定中得到了重述在原始患者样本中，PD1 缺失的 CTCL 显示离体增殖增加。尤其，表达 PD1 的 CTCL 共抑制受体和 T 细胞基因特征的表达增加衰竭，T 细胞的一种功能失调状态，限制了效应器功能。有趣的是，PD1 似乎驱动即使在没有配体的情况下，细胞仍保留持久的耗竭表型，这表明耗尽的 CTCL 具有表观遗传肿瘤抑制程序，该程序在 PD1 缺失的 CTCL 中丢失。此外，我们的初步 RNA-seq 数据确定了 60 个转录因子在 PD1 表达之间差异表达和删除的 CTCL 队列中，许多但不是全部都与肿瘤研究中的 T 细胞耗竭有关模型。因此，在这个提案中，我们的目标是机械地剖析表观遗传和转录 PD1 缺失的 CTCL 样本中侵袭性表型的调节。在目标 1 中，我们将确定是否在表达 PD1 的 CTCL 中上调的转录因子对于促进 CTCL 是必要或充分的精疲力尽。此外，我们还将利用主要患者样本来确定是否逆转每个 CTCL 队列中转录因子的下调/上调可以逆转或增加衰竭表型。在目标 2 中，我们将阐明原发性 CTCL 中 PD1 依赖性表观遗传调节因子结合表观遗传学和转录组数据来识别每个 CTCL 中差异表达的转录因子以公正的方式进行分组。我的总体职业目标是成为一名成功的、独立的研究科学家。该奖学金中提出的严格培训计划将使我能够通过获得研究技能来实现这一目标以及细胞免疫学、癌症信号通路和表观遗传学方面的知识。我将受到博士的指导。 CTCL 专家医师兼科学家 Jaehyuk Choi 和世界著名 T 细胞生物学家 Deyu Fang 博士制定了一项联合培训计划，以培养所有必要的研究技能、沟通技能并促进我的专业发展。该奖学金将拓宽我们对 CTCL 发病机制和 T 细胞的理解疲惫不堪，找出潜在的新颖治疗策略，并为我的未来提供必要的基础作为一名研究科学家的职业。