Interrogating oncogene-dependency and mutation order in FLT3 mutant AML

探究 FLT3 突变 AML 中的癌基因依赖性和突变顺序

基本信息

批准号：
10703473
负责人：
Robert Lyle Bowman
金额：
$ 24.53万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10703473
关键词：
Ablation Acute Myelocytic Leukemia Address Affect Alleles Automobile Driving CRISPR/Cas technology Cells Chemicals Clinical Clinical Trials Clonal Evolution Coculture Techniques Communication DNA Sequence Alteration DNMT3a Dependence Development Disease Disease Progression Doctor of Philosophy Epigenetic Process Event FDA approved FLP recombinase FLT3 gene FLT3 inhibition FLT3 inhibitor Foundations Future Gene Frequency Genes Genetic Genetic Transcription Genomics Goals Grant Head Hematologic Neoplasms Heterogeneity Human In complete remission Intervention Laboratories Lead Lesion Leukemic Cell Link Maintenance Malignant - descriptor Malignant Neoplasms Membrane Memorial Sloan-Kettering Cancer Center Mentors Methods Minor Modeling Molecular Mutate Mutation Myeloid Leukemia NPM1 gene Oncogene Activation Oncogenes Oncogenic Oncology Outcome Pathogenesis Patients Pharmaceutical Preparations Phase Postdoctoral Fellow Predisposition Process Prognostic Marker Protein Tyrosine Kinase Receptor Protein-Tyrosine Kinases Recurrent disease Relapse Reporter Research Research Institute Resistance Resources Role Signal Transduction Site Somatic Mutation System Technical Expertise Testing Therapeutic Treatment Efficacy anticancer research career career development clinically relevant efficacious treatment epigenetic drug epigenome fitness genetic epidemiology genetic variant improved in vivo inhibitor insight leukemia leukemia treatment leukemic transformation leukemogenesis member mouse model mutant novel novel therapeutics patient subsets programs recombinase relapse patients research and development response skills small molecule success therapeutic target tool tool development treatment response tumor microenvironment

项目摘要

PROJECT ABSTRACT/SUMMARY CANDIDATE: I am a postdoctoral fellow in the laboratory of Dr. Ross Levine in the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center. My previous PhD research offered me the opportunity to develop the experimental and computational skills necessary to assess cellular crosstalk in the tumor microenvironment. My current research extends these skills to the study of mutation order, and oncogene-dependency in subpopulations of leukemic cells. To gain insights into these processes I developed novel, multi-recombinase mouse models of oncogene-activation and dependency as well as new lineage tracing tools that allow for functional interrogation of clonal evolution. My proposed research will provide a strong foundation for independent research following the K99 phase of this grant. My long-term career goal is to identify molecular mechanisms driving leukemogenesis, including interactions between AML subclones in vivo and the role of sequential mutational acquisition. To achieve these goals I have developed a career plan that will 1) bolster my technical skills and scientific scope, 2) improve my presentation and communication skills, 3) cultivate professional relationships and networking, and 4) prepare me for mentoring future trainees. RESEARCH: The receptor tyrosine kinase, FLT3, is the most commonly mutated gene in acute myeloid leukemia. Mutations in FLT3 are often found with low variant allele frequency, suggesting these mutations occur as late, subclonal events. Despite their presence as a minor clone, FLT3 mutations are poor prognostic markers and the target of several recently approved clinical compounds. These inhibitors lead to some transient clinical success, yet patients invariably relapse and develop resistant, calling into question the necessity of FLT3 mutation in disease progression. I aim to determine the dependency of FLT3 mutations in disease, and propose methods to assess the functional contributions of subclonal mutations to disease progression. The specific aims are: 1) determining the genomic context for FLT3 oncogene-dependency in AML, 2) identifying novel therapeutic vulnerabilities in FLT3-driven AML, and 3) investigating the role of mutation order and clonal crosstalk in leukemic disease. ENVIRONMENT: The Levine laboratory is a part of the Human Oncology and Pathogenesis Program (HOPP) at Memorial Sloan Kettering Cancer Center, a state of the art cancer research institute. The Levine lab is also a member of the Center for Epigenetic Research, and the primary mentor Dr. Levine, is the head of the Center for Hematologic Malignancies. These affiliations provide a rich set of collaborative, technical and scientific resources to execute the research and career development proposed here.

项目摘要/总结候选人：我是 Ross Levine 博士实验室的人类肿瘤学和纪念斯隆凯特琳癌症中心的发病机制项目。我之前的博士研究为我提供了有机会发展评估细胞串扰所需的实验和计算技能肿瘤微环境。我目前的研究将这些技能扩展到突变顺序的研究，并且白血病细胞亚群中的癌基因依赖性。为了深入了解我开发的这些流程癌基因激活和依赖性的新型多重组酶小鼠模型以及新的谱系追踪允许对克隆进化进行功能询问的工具。我提出的研究将提供强有力的此项资助的 K99 阶段之后的独立研究基金会。我的长期职业目标是确定驱动白血病发生的分子机制，包括体内 AML 亚克隆之间的相互作用以及连续突变获得的作用。为了实现这些目标，我制定了职业计划 1) 增强我的技术技能和科学视野，2) 提高我的演讲和沟通技巧，3) 培养专业关系和网络，4) 为指导未来的学员做好准备。研究：受体酪氨酸激酶 FLT3 是急性髓系细胞中最常见的突变基因白血病。 FLT3 突变通常具有较低的变异等位基因频率，表明这些突变发生较晚的亚克隆事件。尽管 FLT3 突变作为小克隆存在，但预后较差一些最近批准的临床化合物的标志物和靶标。这些抑制剂会导致一些短暂的临床成功，但患者总是会复发并产生耐药性，这引起了人们的质疑 FLT3突变在疾病进展中的必要性。我的目标是确定 FLT3 突变的依赖性疾病，并提出评估亚克隆突变对疾病的功能贡献的方法进展。具体目标是：1) 确定 FLT3 癌基因依赖性的基因组背景 AML，2) 识别 FLT3 驱动的 AML 中新的治疗漏洞，以及 3) 研究白血病中的突变顺序和克隆串扰。环境：莱文实验室是人类肿瘤学和发病机制计划的一部分（HOPP）位于纪念斯隆凯特琳癌症中心，这是一家最先进的癌症研究机构。莱文实验室也是表观遗传学研究中心的成员，主要导师Levine博士是该中心的负责人血液恶性肿瘤中心。这些隶属关系提供了丰富的协作、技术和执行此处提出的研究和职业发展的科学资源。