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: 10016223
• 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/10016223
• 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; 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/antagonist; insight; lectures; leukemia; leukemogenesis; novel; novel therapeutic intervention; novel therapeutics; 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.

项目概要 这项研究计划由 Seongseok Yun 博士准备，描述了一个为期五年的培训计划 癌症研究学术生涯的发展。云博士在分子生物学领域拥有多年经验 药理学和癌症生物学，特别关注血液肿瘤。云博士最近开始 研究 TFEB 在克利夫兰博士的急性髓系白血病 (AML) 发展和维持中的作用 实验室。云博士发现MYC抑制TFEB，TFEB表达促进骨髓分化 和细胞死亡。云博士现在提出了 MYC 中 TFEB 的详细分子和细胞生物学特征- 驱动的反洗钱。 MYC 癌蛋白是一种转录因子，可协调糖酵解相关基因的表达， 谷氨酰胺分解和营养物质运输，从而促进向有氧糖酵解的转变。虽然临床前研究 已经表明 MYC 过度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 表达诱导骨髓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。对此 最后，云博士将利用新工具研究 TFEB 对 Rosa26-LSL-MYC 小鼠 AML 抑制的影响 移植模型。云博士将评估 MYC 是否作为直接 TFEB 转录抑制因子发挥作用，以及 检查 TFEB 表达是否会损害体内 MYC 驱动的 AML 的发育和维持。此外，他还将 描述 TFEB 肿瘤抑制机制的特征，特别关注其在表观遗传中的作用 调制。这些分析将揭示 TFEB 在 AML 中的肿瘤抑制功能，并提供新的思路 治疗方法。 云博士致力于生物医学研究事业，并概述了全面的职业发展 计划以实现他的独立目标。克利夫兰博士的实验室将为云博士提供机会 获得额外的专业知识，成为一名全面的医师科学家。云博士将从莫菲特和 南佛罗里达大学的激励性环境是通过与优秀教师的密切互动和多核心人员创造的 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 莫菲特和南佛罗里达大学的会议、教育研讨会和课程。此外，指导和建议 来自云博士的顾问委员会和他的合作者 - 血液恶性肿瘤领域的领导者 拥有支持学员向独立过渡的良好记录——将极大地促进他 过渡到独立调查员职位。