Tumor suppressor roles of TFEB in the development and maintenance of myeloid leukemia

TFEB 在髓系白血病发生和维持中的抑癌作用

• 批准号: 10460224
• 负责人: Seongseok Yun
• 金额: $ 23.88万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-11 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460224
• 关键词: Acute Myelocytic Leukemia; Advisory Committees; Automobile Driving; Autophagocytosis; Biogenesis; Biological; Biomedical Research; Cancer Biology; Cell Death; Cells; Cessation of life; Chromosome abnormality; Clonal Expansion; Core Facility; DNA; Databases; Development; Diagnosis; Drug resistance; Educational workshop; Environment; Enzymes; Epigenetic Process; FLT3 gene; FRAP1 gene; Faculty; Gene Expression; Glycolysis; Goals; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hydroxylation; Impairment; In Vitro; Laboratories; Light; Lysosomes; MLL-AF9; Maintenance; Malignant Neoplasms; Molecular; Molecular Abnormality; Molecular Genetics; Molecular Target; Mus; Myelogenous; Myeloid Cells; Myeloid Leukemia; Nutrient; Oncogenic; Oncoproteins; Outcome; PML-RARalpha protein; Pathogenesis; Pathway interactions; Patients; Persons; Pharmacology; Physicians; Positioning Attribute; Process; Program Development; Proto-Oncogene Proteins c-myc; Recycling; Regulation; Regulator Genes; Research; Research Personnel; Research Project Summaries; Research Proposals; Research Support; Residual state; Resistance; Role; SEER Program; Scientist; Series; Signal Transduction; Survival Rate; Therapeutic; Training Programs; Transcription Repressor; Transcriptional Regulation; Tumor Suppression; Tumor Suppressor Proteins; Work; adult leukemia; aerobic glycolysis; anticancer research; base; bcr-abl Fusion Proteins; career; career development; epigenetic regulation; experience; improved; in vivo; in vivo Model; inhibitor; insight; lectures; leukemia; leukemogenesis; novel; novel therapeutic intervention; overexpression; preclinical study; progenitor; programs; survival outcome; symposium; targeted treatment; tool; transcription factor; transplant model; treatment strategy; tumor

PROJECT SUMMARY This research proposal, prepared by Dr. Seongseok Yun, describes a five-year training program for the development of an academic career in cancer research. Dr. Yun has several years of experience in molecular pharmacology and cancer biology specifically focusing on hematologic neoplasms. Dr. Yun has recently begun to study the role of TFEB in acute myeloid leukemia (AML) development and maintenance in Dr. Cleveland’s laboratory. Dr. Yun identified that MYC represses TFEB and TFEB expression promotes myeloid differentiation and cell death. Dr. Yun now proposes a detailed molecular and cell biological characterization of TFEB in MYC- driven AML. MYC oncoprotein is a transcriptional factor that coordinates the expression of genes involve in glycolysis, glutaminolysis, and nutrient transport, thus promoting a shift to aerobic glycolysis. Although preclinical studies have shown that MYC overexpression is sufficient to induce AML in mice, how MYC drives AML is not resolved. Based upon preliminary observations that TFEB expression induces myeloid differentiation and cell death, Dr. Yun proposes to characterize tumor suppressive role of TFEB in MYC-driven AML in vivo and in vitro. To this end, Dr. Yun will utilize novel tools to study the effect of TFEB on AML suppression in Rosa26-LSL-MYC mouse transplant model. Dr. Yun will assess whether MYC functions as a direct TFEB transcriptional repressor and examine if TFEB expression impairs development and maintenance of MYC-driven AML in vivo. Also, he will characterize the mechanisms of TFEB tumor suppression, specifically focusing on it roles in the epigenetic modulation. These analyses will shed light on the tumor suppressive function of TFEB in AML and provide novel therapeutic approaches. Dr. Yun is committed to a career in biomedical research and has outlined a comprehensive Career Development program to achieve his goal of independence. Dr. Cleveland’s laboratory will provide Dr. Yun with the opportunity to gain additional expertise to become a well-rounded physician scientist. Dr. Yun will benefit from Moffitt and USF’s stimulating environment that is created by close interactions with outstanding faculty and by multiple core facilities that provide excellent research support. This program includes lectures and seminar series, scientific conferences, and educational workshops and courses at Moffitt and USF. In addition, the guidance and advice from Dr. Yun’s advisory committee and his collaborators - leaders in the field of hematological malignancies who have proven track record of supporting the transition of their trainees to independence – will greatly facilitate his transition to an independent investigator position.

项目摘要 这份由Seongseok Yun博士编写的研究计划描述了一个为期五年的培训计划， 发展癌症研究的学术生涯。Yun博士在分子生物学领域有多年的经验， 药理学和癌症生物学，特别关注血液肿瘤。尹博士最近开始 研究TFEB在急性髓细胞白血病（AML）发展和维持中的作用， 实验室Yun博士发现MYC抑制TFEB，TFEB表达促进骨髓分化 和细胞死亡。Yun博士现在提出了MYC中TFEB的详细分子和细胞生物学特征， 驱动AML MYC癌蛋白是一种转录因子，协调糖酵解相关基因的表达， 氨解和营养转运，从而促进有氧糖酵解的转变。虽然临床前研究 已经表明MYC过表达足以在小鼠中诱导AML，但MYC如何驱动AML尚未解决。 基于TFEB表达诱导髓样分化和细胞死亡的初步观察，Dr。 Yun提出在体内和体外表征TFEB在MYC驱动的AML中的肿瘤抑制作用。本 最后，Yun博士将利用新的工具研究TFEB对Rosa 26-LSL-MYC小鼠AML抑制的作用 移植模型Yun博士将评估MYC是否作为直接TFEB转录抑制因子发挥作用， 检查TFEB表达是否损害体内MYC驱动的AML的发展和维持。而且，他会 描述TFEB肿瘤抑制的机制，特别关注它在表观遗传学中的作用。 调变这些分析将阐明TFEB在AML中的肿瘤抑制功能，并提供新的治疗方法。 治疗方法。 博士Yun致力于生物医学研究事业，并概述了全面的职业发展 计划，以实现其独立的目标。克利夫兰博士的实验室将为云博士提供 以获得更多的专业知识，成为一个全面的医生科学家。云博士将受益于莫菲特和 USF的刺激环境是由与优秀教师的密切互动和多个核心创造的 提供卓越研究支持的设施。该计划包括讲座和研讨会系列，科学 会议，并在莫菲特和USF的教育研讨会和课程。此外，指导和建议 来自云博士的咨询委员会和他的合作者-血液恶性肿瘤领域的领导者， 在支持受训人员向独立过渡方面有良好的记录-这将大大有助于他 过渡到独立调查员职位。