Interrogating oncogene-dependency and mutation order in FLT3 mutant AML

项目摘要/摘要 候选人：我是罗斯·莱文博士实验室的博士后，研究人类肿瘤学和 纪念斯隆·凯特琳癌症中心的致病计划。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 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 新的癌基因激活和依赖的多重重组小鼠模型以及新的谱系追踪 允许对克隆进化进行功能性询问的工具。我提出的研究将提供一个强有力的 这笔赠款K99阶段之后的独立研究基金会。我的长期职业目标是 识别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 以及顺序突变获取的作用。为了实现这些目标，我制定了一份职业规划 将1)增强我的技术技能和科学视野，2)提高我的演讲和沟通能力，3) 培养职业关系和人际网络，并为指导未来的实习生做好准备。 研究：受体酪氨酸激酶，Flt3，是急性髓系最常见的突变基因 白血病。在Flt3中经常发现变异等位基因频率低的突变，这表明这些突变 以晚期亚克隆事件的形式发生。尽管Flt3是一个小克隆，但它们的突变预示着不良的预后。 标记物和最近批准的几种临床化合物的靶标。这些抑制物导致了一些 短暂的临床成功，但患者总是复发并产生耐药性，这让人对 Flt3基因突变在疾病进展中的必要性。我的目标是确定Flt3突变对 疾病，并提出评估亚克隆突变对疾病的功能贡献的方法 进步。具体目的是：1)确定Flt3癌基因依赖的基因组环境。 AML，2)确定Flt3驱动的AML的新的治疗脆弱性，以及3)调查 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学和病理学计划的一部分 (霍普)在纪念斯隆·凯特琳癌症中心，这是一个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，主要导师莱文博士是 恶性血液病中心。这些合作关系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。

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.