Characterizing the role of MARCH5 in apoptosis regulation in acute myeloid leukemia

表征 MARCH5 在急性髓系白血病细胞凋亡调节中的作用

基本信息

批准号：
10473763
负责人：
Shan Lin
金额：
$ 13.61万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-23 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10473763
关键词：
Acute Myelocytic Leukemia Acute leukemia Advisory Committees Apoptosis Apoptosis Regulation Gene Apoptotic Award BCL2 gene BCL2L1 gene Biochemical Biological CRISPR screen CRISPR/Cas technology Cell Death Cell physiology Clinic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Communities Critical Thinking Dana-Farber Cancer Institute Data Dependence Development Dropout Elderly Essential Genes Exhibits Family member Genetic Goals Growth Hematologic Neoplasms In Vitro Intervention Knock-out Knowledge Laboratories MCL1 gene MDM2 gene Maintenance Malignant Neoplasms Mediating Mentorship Mitochondria Molecular Oncogenic Patients Pediatric Oncology Pharmaceutical Preparations Pharmacology Pre-Clinical Model Prognosis Protein Family Proteins Regulation Research Resistance Resistance development Resources Role Solid Specificity Stress Substrate Interaction System Technical Expertise Therapeutic Training Translating Ubiquitin Ubiquitin-Activating Enzymes Ubiquitin-Conjugating Enzymes Ubiquitination Vision Xenograft Model acute myeloid leukemia cell cancer cell cancer survival career cell growth clinical application collaborative environment frontier functional genomics genetic regulatory protein human model improved in vivo inhibitor insight leukemia leukemia treatment leukemogenesis multicatalytic endopeptidase complex novel novel therapeutic intervention novel therapeutics patient subsets pediatric department prevent programs skills targeted cancer therapy targeted treatment therapeutic development therapeutic target translational potential tumor ubiquitin-protein ligase

项目摘要

Project Summary Acute myeloid leukemia (AML) remains a devastating illness, with a clear need for the development of novel anti-leukemic therapy. Inhibition of anti-apoptotic BCL2 family proteins to directly stimulate apoptosis provides a feasible therapeutic strategy for treating AML. Venetoclax, a BCL2-specific inhibitor, has exhibited promising anti-leukemic effect in a subset of patients with AML. However, resistance to venetoclax can develop. Therefore, identification of other synergistic targets attacking the apoptosis defense system is needed to enhance the efficacy of anti-BCL2 therapy in AML. Integrating functional genomics and xenograft models, I developed an in vivo CRISPR-Cas9 screen approach to identify MARCH5, a RING-type ubiquitin E3 ligase, as an essential gene for AML cell growth. My preliminary studies showed that MARCH5 is a critical regulator of apoptosis in AML cells. MARCH5-depleted AML cells display increased apoptotic cell death and enhanced sensitivity to venetoclax, suggesting that MARCH5 can serve as a potential therapeutic target for AML. The goal of this proposal is to evaluate the translational potential of targeting MARCH5 as an AML therapy, and investigate the mechanism of action of MARCH5 protein and its related network to provide biological insights for the development of therapeutic strategies targeting MARCH5. The Specific Aims are: (1) Determine the domains of the MARCH5 protein critical for preventing apoptosis in AML; (2) Evaluate the therapeutic potential of MARCH5 inhibition in preclinical models of AML; and (3) Identify the key regulatory proteins critical for MARCH5-mediated apoptosis regulation. This study will deepen our understanding of the apoptosis regulation and its clinical application in AML, uncover novel therapeutic opportunities for targeting MARCH5 and AML, and provide a synergistic approach to enhance the efficacy of venetoclax in AML and potentially other malignancies. I am a postdoctoral research fellow in the laboratory of Dr. Kimberly Stegmaier at the Department of Pediatric Oncology at Dana-Farber Cancer Institute (DFCI). My current research focuses on identification and characterization novel dependencies in acute leukemia, and the application of these knowledge to the development of novel therapeutic approaches. My long-term career goal is to establish a research program focusing on understanding the molecular mechanisms of leukemogenesis and leukemia vulnerabilities, with a strong commitment to translate basic scientific discoveries into the clinic. The proposed research will form a solid platform from which I can establish my own research group by the end of the K99 Award period. I have developed a focused training plan to accomplish my goal: (1) expand my scientific knowledge and vision; (2) sharpen my critical thinking and technical skills; and (3) develop and strengthen my professional skills. With the mentorship of Dr. Kimberly Stegmaier, deep support from my scientific advisory committee, and rich resource and collaborative environment offered by DFCI and the Harvard community, I will be well prepared for the transition into the independence.

项目概要急性髓系白血病（AML）仍然是一种毁灭性的疾病，显然需要开发新的治疗方法抗白血病治疗。抑制抗凋亡 BCL2 家族蛋白以直接刺激细胞凋亡提供了治疗 AML 的可行治疗策略。 Venetoclax 是一种 BCL2 特异性抑制剂，表现出良好的前景对一部分 AML 患者具有抗白血病作用。然而，可能会产生对维奈托克的耐药性。所以，需要识别攻击细胞凋亡防御系统的其他协同靶点以增强抗 BCL2 疗法在 AML 中的疗效。整合功能基因组学和异种移植模型，我开发了一种体内 CRISPR-Cas9 筛选方法鉴定 MARCH5（一种环型泛素 E3 连接酶）作为必需基因用于 AML 细胞生长。我的初步研究表明，MARCH5 是 AML 细胞凋亡的关键调节因子。 MARCH5 耗尽的 AML 细胞显示凋亡细胞死亡增加和对 Venetoclax 的敏感性增强，表明MARCH5可以作为AML的潜在治疗靶点。该提案的目标是评估以 MARCH5 为靶标的 AML 疗法的转化潜力，并研究其机制 MARCH5蛋白及其相关网络的作用为治疗药物的开发提供生物学见解针对 3 月 5 日的策略。具体目标是： (1) 确定 MARCH5 蛋白关键域用于预防 AML 中的细胞凋亡； (2) 评估MARCH5抑制在临床前模型中的治疗潜力反洗钱； (3) 鉴定对 MARCH5 介导的细胞凋亡调节至关重要的关键调节蛋白。这研究将加深我们对细胞凋亡调控及其在 AML 中的临床应用的理解，揭示新的机制针对 MARCH5 和 AML 的治疗机会，并提供协同方法来增强 Venetoclax 在 AML 和其他潜在恶性肿瘤中的疗效。我是儿科Kimberly Stegmaier博士实验室的博士后研究员丹娜—法伯癌症研究所 (DFCI) 的肿瘤学。我目前的研究重点是识别和描述急性白血病的新依赖性，并将这些知识应用于开发新的治疗方法。我的长期职业目标是建立一个研究计划专注于了解白血病发生和白血病脆弱性的分子机制，坚定致力于将基础科学发现转化为临床。拟议的研究将形成一个坚实的在 K99 奖期结束时我可以通过这个平台建立自己的研究小组。我已经开发了一个有针对性的培训计划来实现我的目标：（1）扩展我的科学知识和视野； (2) 磨砺我的批判性思维和技术技能； (3) 发展和加强我的专业技能。在师徒的指导下 Kimberly Stegmaier 博士的指导、我的科学顾问委员会的大力支持以及丰富的资源和 DFCI 和哈佛社区提供的协作环境，我将为过渡做好充分准备进入独立。