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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.

项目总结/文摘