The role of ZEB1 mutations in cutaneous T cell lymphoma

ZEB1突变在皮肤T细胞淋巴瘤中的作用

基本信息

批准号：
8966994
负责人：
Jaehyuk Choi
金额：
$ 1.57万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8966994
关键词：
Achievement Adult T-Cell Leukemia/Lymphoma Advisory Committees Apoptosis Binding Binding Sites Bioinformatics Blood Boxing CD4 Positive T Lymphocytes CD47 gene CD8B1 gene Cause of Death Cell Line Cell physiology Cells ChIP-seq Clinical Complex Cutaneous Dermatology Disease Down-Regulation Educational Curriculum Epigenetic Process Exhibits Foundations Funding Gene Expression Profile Gene Targeting Genes Genetic Genetic Recombination Genetic Transcription Germ-Line Mutation Goals Health Hereditary Disease Homeobox Homing Human Immune Immune system Immunobiology Immunophenotyping Immunosuppression In Vitro Interleukin-13 Interleukin-4 Interleukin-5 K-Series Research Career Programs Laboratories LacZ Genes Lymphoma Lymphomagenesis Lymphopenia Malignant - descriptor Malignant Neoplasms Mediating Mentors Mentorship Mus Mutation Mycosis Fungoides Non-Hodgkin&apos s Lymphoma Non-Malignant Organ Pathogenesis Pathway interactions Patient Care Patients Peripheral Phenotype Physicians Production Protein Binding Qualifying Receptor Activation Recurrence Reporting Research Research Personnel Resistance Resources Role Sampling Scientist Sezary Syndrome Skin Small Interfering RNA Staging Structure Sum T-Cell Lymphoma T-Cell Proliferation T-Cell Receptor T-Lymphocyte Time Tissues Training Transcript Transforming Growth Factor beta Tumor Suppressor Proteins United States National Institutes of Health Visceral Zinc Fingers base career cohort cytokine exome sequencing experience genome sequencing genome-wide immunosuppressed in vivo loss of function mutation lymph nodes mouse model mutant neoplastic cell novel novel therapeutics professor promoter statistics thymocyte transcription factor transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): The NIH K08 mentored career development award provides the necessary foundation for me to fulfill my long- term career goal of becoming an independently funded translational investigator with a clinical and scientific focus on cutaneous T cell lymphoma (CTCL). CTCL is an incurable non-Hodgkin lymphoma of the skin-homing CD4+ T cell. Patients initially present with lymphoma cells exclusively in the skin; however, as disease progresses, the tumor cells spread to the blood, lymph nodes, and visceral organs. The malignant T cell clone produces cytokines that dramatically alter the immune system; correspondingly, a common cause of death from CTCL is fatal immunosuppression. As an Assistant Professor at Yale, I have focused my clinical efforts on caring for patients with this malignancy. Since cancer is fundamentally a genetic disease, I have focused my laboratory efforts on identifying the genetic basis of CTCL. To our knowledge, I have performed the first exome sequencing of CTCLs. Sequencing 40 CTCLs from patients with advanced leukemic disease, we have identified the landscape of cancer promoting mutations with high clarity. In particular, we found that ZEB1 is a critical tumor suppressor in CTCL, subject to loss-of-function mutations in 65% of patients. ZEB1 encodes a zinc finger E-box binding homeobox transcription factor that interestingly has putative binding sites at multiple genes thought to mediate CTCL's distinctive immune phenotype. Highlighting its tumor suppressor function in T cells, 84% of mice with germline mutations in ZEB1 spontaneously develop CD4+ peripheral T cell lymphomas (PTCL). In this proposal, our objectives are to elucidate the role of ZEB1 mutations in promoting the malignant transformation of CD4+ T cells. In Aim 1, we will determine the time of onset of ZEB1 mutations in CTCL by sequencing ZEB1 in early-stage skin-limited CTCL and whole genome sequencing ZEB1 in leukemic CTCL. In Aim 2, we will identify the transcriptional targets of ZEB1 in CTCL, using 1) RNA-Seq to find transcripts that are altered in ZEB1-/- CTCL and 2) ChIP-Seq to identify ZEB1's binding sites in ZEB1-replete CD4+ T cells. In Aim 3, we will isolate the contribution of ZEB1 mutations to lymphomagenesis in vivo by carefully analyzing the phenotypes and transcriptomes of ZEB1-/- murine PTCLs. To achieve the expertise necessary for the successful achievement of the proposed aims, I have committed to a comprehensive training plan utilizing the extensive scientific and clinical resources available in Yale's world-renowned Departments of Genetics, Immunobiology, and Dermatology. I will follow a structured curriculum consisting of seminars and coursework in immunobiology, statistics, and bioinformatics. In addition, I will be closely mentored by a highly qualified primary mentor (Dr. Richard Lifton) and an advisory committee, which was carefully chosen for their proven track record for mentorship and non-overlapping expertise in CTCL, epigenetic, and immunobiology. In sum, this proposal will hopefully elucidate a critical mechanism underlying CTCL pathogenesis while preparing me for a successful independent career as a physician scientist.

描述（由应用程序提供）：NIH K08指导的职业发展奖为我提供了必要的基础，以实现我的长期职业目标，即成为一名独立资助的翻译研究员，临床和科学专注于皮肤T细胞淋巴瘤（CTCL）。 CTCL是一种无法治愈的皮肤CD4+ T细胞的非霍奇金淋巴瘤。患者最初仅在皮肤中出现淋巴瘤细胞。然而，随着疾病的发展，肿瘤细胞扩散到血液，淋巴结和内脏器官。恶性T细胞克隆会产生极大地改变免疫系统的细胞因子。相应地，CTCL死亡的常见原因是致命的免疫抑制。作为耶鲁大学的助理教授，我将临床工作集中在照顾这种恶性肿瘤的患者上。由于癌症从根本上是一种遗传疾病，因此我将实验室的努力集中在确定CTCL的遗传基础上。据我们所知，我进行了CTCL的第一个外显子组测序。从患有晚期白血病疾病的患者的40个CTCL进行测序，我们已经确定了癌症促进突变的景观。特别是，我们发现Zeb1是CTCL中的一个关键肿瘤抑制剂，在65％的患者中受功能丧失突变。 Zeb1编码一个锌指的E-box结合同源蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白盒转录因子，有趣的是，该因子在多个基因的假定结合位点被认为介导CTCL的独特免疫表型。突出了其在T细胞中的肿瘤抑制功能，其中84％的小鼠具有生殖线突变，自发性地发展为CD4+外周T细胞淋巴瘤（PTCL）。在此提案中，我们的目标是阐明Zeb1突变在促进CD4+ T细胞的恶性转化中的作用。在AIM 1中，我们将通过对早期皮肤有限的CTCL和整个基因组测序ZEB1在白血病CTCL中测序ZEB1来确定CTCL中ZEB1突变的发作时间。在AIM 2中，我们将使用1）RNA-Seq在CTCL中识别Zeb1的转录靶标，以查找在Zeb1 - / - CTCL和2）ChIP-Seq中更改的转录物，以识别Zeb1的结合位点ZEB1-REPLETE CD4+ T细胞中的Zeb1结合位点。在AIM 3中，我们将通过仔细分析Zeb1 - / - 鼠PTCL的表型和转录组来隔离Zeb1突变对体内淋巴作用的贡献。为了实现成功实现拟议目标所必需的专业知识，我致力于一项全面的培训计划，利用耶鲁大学世界著名部门的遗传学，免疫生物学和皮肤病学的广泛科学和临床资源。我将遵循一个结构化课程，该课程包括免疫生物学，统计和生物信息学方面的精神分裂和课程。此外，我将通过一位高素质的初级精神（Richard Lifton博士）和一个咨询委员会的核对，该委员会因其在CTCL，表观遗传学和免疫生物学方面的心态和非重叠专业知识而精心挑选。总而言之，该提议将有望阐明CTCL发病机理的基本重要机制，同时为我做好了成功作为物理科学家的独立职业。