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

• 批准号: 10284146
• 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
• 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/10284146
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Advisory Committees; Apoptosis; Apoptosis Regulation Gene; Apoptotic; Award; BCL1 Oncogene; BCL2 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/antagonist; 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; tumor; ubiquitin-protein ligase

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.

项目摘要 急性髓性白血病（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细胞凋亡BCL 2家族蛋白以直接刺激细胞凋亡提供了一种新的治疗方法。 治疗AML的可行治疗策略。Venetoclax是一种BCL 2特异性抑制剂， 在AML患者亚组中的抗白血病作用。然而，对venetoclax的耐药性可能会发展。因此，我们认为， 需要鉴定攻击细胞凋亡防御系统的其他协同靶点，以增强细胞凋亡防御系统。 AML中抗BCL 2治疗的疗效。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MARCH 5，一种RING型泛素E3连接酶，作为必需基因 AML细胞的生长。我的初步研究表明，MARCH 5是AML细胞凋亡的关键调节因子。 MARCH 5耗尽的AML细胞显示出增加的凋亡性细胞死亡和增强的对维奈托克的敏感性， 这表明MARCH 5可以作为AML的潜在治疗靶点。本提案的目的是 评估靶向MARCH 5作为AML治疗的翻译潜力，并研究其机制。 MARCH 5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日的战略。具体目的是：（1）确定MARCH 5蛋白的关键结构域 （2）在临床前模型中评估MARCH 5抑制的治疗潜力 急性髓细胞白血病;和（3）确定对MARCH 5介导的细胞凋亡调节至关重要的关键调节蛋白。这 本研究将加深我们对细胞凋亡调控及其在AML中的临床应用的认识， 靶向MARCH 5和AML的治疗机会，并提供协同方法来增强 维奈托克在AML和其他潜在恶性肿瘤中的疗效。 我是儿科系Kimberly Stegmaier博士实验室的博士后研究员， Dana-Farber癌症研究所（DFCI）我目前的研究重点是识别和 描述急性白血病中的新依赖性，以及这些知识在 开发新的治疗方法。我的长期职业目标是建立一个研究项目 重点是了解白血病发生和白血病脆弱性的分子机制， 坚定地致力于将基本科学发现转化为临床。这项研究将形成一个坚实的基础。 我可以在K99奖结束前建立自己的研究小组。I have developed 一个有针对性的培训计划，以实现我的目标：（1）扩大我的科学知识和视野;（2）提高我的 批判性思维和技术技能;（3）发展和加强我的专业技能。有了导师 Kimberly Stegmaier博士，我的科学顾问委员会的大力支持，以及丰富的资源和 通过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。