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.

项目摘要/摘要皮肤T细胞淋巴瘤（CTCL）是一种无法治愈的皮肤归巢T细胞的无霍奇金淋巴瘤。临床 CTCL的结果高度异质，一些患者存活<6个月，而其他患者则在10年中> 10年阶段与患有晚期疾病的患者相匹配。驱动疾病异质性的分子机制结果仍然很少了解。我们采用了整个基因组测序，RNA测序和在大量的主要患者样本中进行功能测定，以了解CTCL的遗传基础。我们已经确定了pDCD1的缺失，PDCD1是编码共抑制受体PD1的基因，是一个单基因驱动 CTCL疾病侵略和表型。在多机构队列中对CTCL的分析表明PD1 缺失预测患者的总体生存率明显较差。这在我们的功能测定中概括了在初级患者样品中，表现出具有PD1缺失的CTCL会增加体内增殖。尤其， PD1表达CTCL的共抑制受体和T细胞的基因特征的表达增加精疲力尽，在T细胞中限制效应子功能的功能失调。有趣的是，PD1似乎驱动了即使没有配体的情况，也由细胞保留的耐用衰竭表型，这表明耗尽的CTCL具有表观遗传抑制剂程序，该程序在PD1删除的CTCL中丢失。此外，我们的初步RNA-seq数据鉴定了60个转录因子，在表达PD1之间差异表达和删除的CTCL队列，许多但并非全部与肿瘤的研究有关型号。因此，在此提案中，我们旨在机械剖析表观遗传和转录 PD1删除的CTCL样品中侵袭性表型的调节。在AIM 1中，我们将确定是否在表达CTCL的PD1中上调的转录因子对于促进CTCL是必需的或足够的精疲力尽。此外，我们还将利用初级患者样本来确定每个CTCL队列中转录因子的下调/上调可以逆转或增加疲惫表型。在AIM 2中，我们将阐明主要CTCL中的PD1依赖性表观遗传调节剂，我们将结合表观遗传学和转录组数据，以识别每个CTCL中差异表达的转录因子队列以公正的方式。我的整体职业目标是成为一名成功的独立研究科学家。该奖学金中提出的严格培训计划将使我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的知识。我将得到博士的指导。 CTCL的专家医师科学家Jaehyuk Choi和世界知名的T细胞生物学家Deyu Fang博士已经制定了一个联合培训计划，以发展所有必要的研究技能，沟通技巧并促进我专业发展。该奖学金将扩大我们对CTCL发病机理和T细胞的理解疲惫，确定潜在的新型治疗策略，并为我的未来提供必要的基础作为研究科学家的职业。