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：
10669825
负责人：
Robert Lyle Bowman
金额：
$ 24.9万
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/10669825
关键词：
Ablation Acute Myelocytic Leukemia Address Affect Alleles Automobile Driving CRISPR/Cas technology Cells 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 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 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 chemical genetics clinically relevant efficacious treatment epigenetic drug epigenome fitness genetic epidemiology genetic variant improved in vivo inhibitor insight leukemia leukemic transformation leukemogenesis member mouse model mutant novel novel therapeutics 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/摘要候选人：我是Ross Levine博士实验室的博士后研究员，纪念斯隆·克特林癌症中心的发病机理计划。我以前的博士学位研究给了我开发评估细胞串扰所需的实验和计算技能的机会肿瘤微环境。我目前的研究将这些技能扩展到突变顺序的研究，以及白血病细胞亚群中的癌基因依赖性。为了了解我开发的这些过程新颖的多种癌症激活和依赖性的多组合酶小鼠模型以及新的谱系跟踪允许克隆进化的功能询问的工具。我提出的研究将为强大本赠款的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的分子机制，包括体内AML亚克隆之间的相互作用以及顺序突变的作用。为了实现这些目标，我制定了一个职业计划会1）增强我的技术技能和科学范围，2）提高我的演示和沟通技巧，3）建立专业关系和网络，以及4）为我的指导未来的学员做好准备。研究：受体酪氨酸激酶FLT3是急性髓样中最常见的突变基因白血病。 FLT3中的突变通常以低变异等位基因频率发现，表明这些突变发生在迟到的下克隆事件。尽管它们是次要克隆的存在，但FLT3突变还是不良的预后标记和几种最近批准的临床化合物的靶标。这些抑制剂导致一些短暂的临床成功，但患者总是复发并发展抗性，质疑疾病进展中FLT3突变的必要性。我的目的是确定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。具体目的是：1）确定FLT3癌基因依赖性的基因组环境 AML，2）确定FLT3驱动的AML中新型的治疗漏洞，以及3）研究的作用白血病疾病中的突变顺序和克隆串扰。环境：莱文实验室是人类肿瘤和发病机理计划的一部分（HOPP）在最先进的癌症研究所的纪念斯隆·凯特林癌症中心。莱文实验室也是表观遗传研究中心的成员，主要导师莱文博士是血液系统恶性肿瘤中心。这些隶属关系提供了丰富的协作，技术和科学资源以执行此处提出的研究和职业发展。