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

• 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
• 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

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博士人类肿瘤学实验室的博士后研究员， Memorial Sloan Kettering癌症中心的发病机制计划。我之前的博士研究为我提供了 有机会发展必要的实验和计算技能，以评估蜂窝串扰在 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， 白血病细胞亚群中的癌基因依赖性。为了深入了解这些过程， 癌基因激活和依赖性以及新谱系追踪的新型多重组酶小鼠模型 这些工具允许对克隆进化进行功能性询问。我提出的研究将提供一个强有力的 该基金会在K99阶段之后进行独立研究。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 以及顺序突变获得的作用。为了实现这些目标，我制定了一个职业规划， 我将1）加强我的技术技能和科学范围，2）提高我的演讲和沟通技巧，3） 培养专业关系和网络，以及4）为指导未来的学员做好准备。 研究：受体酪氨酸激酶FLT 3是急性髓系白血病中最常见的突变基因。 白血病FLT 3的突变通常以低变异等位基因频率发现，表明这些突变 作为晚期亚克隆事件发生。尽管FLT 3突变作为次要克隆存在，但其预后不良 标记物和最近批准的几种临床化合物的靶点。这些抑制剂导致一些 短暂的临床成功，但患者总是复发并产生耐药性， FLT 3突变在疾病进展中的必要性。我的目标是确定FLT 3突变在 疾病，并提出方法，以评估亚克隆突变的功能性贡献的疾病 进展具体目标是：1）确定FLT 3癌基因依赖性的基因组背景， AML，2）在FLT 3驱动的AML中识别新的治疗漏洞，以及3）研究 突变顺序和克隆串扰。 环境：Levine实验室是人类肿瘤学和发病机制计划的一部分 （HOPP）在纪念斯隆凯特琳癌症中心，最先进的癌症研究机构。Levine实验室 也是表观遗传学研究中心的成员，主要导师莱文博士是该中心的负责人。 血液肿瘤中心。这些附属机构提供了一套丰富的协作，技术和 科学资源，以执行这里提出的研究和职业发展。