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

项目总结 这份研究提案由Seongseok Yun博士准备，描述了一项为期五年的培训计划， 癌症研究学术生涯的发展。云博士在分子方面有几年的经验 专门研究血液肿瘤的药理学和癌症生物学。云博士最近开始 研究TFEB在急性髓系白血病(AML)发生和维持中的作用 实验室。Yun博士发现MYC抑制TFEB，TFEB表达促进髓系分化 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- 被驱使的AML。 MYC癌蛋白是一种转录因子，协调糖酵解相关基因的表达， 谷氨酰胺分解和养分运输，从而促进向有氧糖酵解的转变。尽管临床前研究 已经证明MYC的过度表达足以在小鼠中诱导AML，但MYC如何驱动AML尚未解决。 根据初步观察，TFEB的表达诱导髓系分化和细胞死亡，Dr。 Yun建议在体内和体外表征TFEB在MYC驱动的AML中的肿瘤抑制作用。对这件事 最后，Yun博士将利用新的工具研究TFEB对rosa26-LSL-MYC小鼠AML抑制的影响 移植模型。Yun博士将评估MYC是否发挥直接TFEB转录抑制因子和 检测TFEB表达是否损害MYC驱动的AML在体内的发展和维持。此外，他还会 描述TFEB抑制肿瘤的机制，特别是它在表观遗传学中的作用 调制。这些分析将有助于阐明TFEB在AML中的抑瘤作用，并提供新的研究方向 治疗方法。 云博士致力于生物医学研究的事业，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 以获得更多的专业知识，成为一名全面的内科科学家。云博士将受益于莫菲特和 USF的激励环境是由与优秀教师的密切互动和多个核心创造的 提供出色研究支持的设施。该计划包括系列讲座和研讨会，科学的 在莫菲特和美国联邦大学举行的会议、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 已经证明支持他们的实习生向独立过渡的记录将极大地促进他的 过渡到独立调查员的职位。

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.