Dissecting the role of clonal evolution in NPM1-mutant AML

剖析克隆进化在 NPM1 突变 AML 中的作用

• 批准号: 10668543
• 负责人: Linde A Miles
• 金额: $ 24.9万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668543
• 关键词: Acute Myelocytic Leukemia; Alleles; Architecture; Biology; Cell Surface Proteins; Cells; Clinical; Clinical Data; Clonal Evolution; Clustered Regularly Interspaced Short Palindromic Repeats; Communication; Cytotoxic Chemotherapy; DNA Sequence Alteration; DNA sequencing; Data; Dependence; Development; Disease; Disease model; Doctor of Philosophy; Environment; Epigenetic Process; Event; Evolution; FLT3 gene; Focus Groups; Fostering; Gene Expression; Gene Frequency; Generations; Genes; Genetic; Genetic Fingerprintings; Genetic Transcription; Genomics; Goals; Grant; Hematologic Neoplasms; Hematopoietic; Hematopoietic stem cells; Human; Impairment; Institution; Lead; Leadership; Leukemic Cell; Malignant - descriptor; Malignant Neoplasms; Medicine; Memorial Sloan-Kettering Cancer Center; Menin; Modeling; Molecular; Molecular Profiling; Mutagenesis; Mutate; Mutation; Myelogenous; NPM1 gene; Oncogenic; Oncology; Output; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pattern; Penetrance; Phase; Phenotype; Postdoctoral Fellow; Pre-Clinical Model; Protein Analysis; Proteins; RNA; Research; Resolution; Resources; Role; Sampling; Services; Signal Transduction; Structure; Study models; Technical Expertise; Techniques; Therapeutic; Therapeutic Intervention; adult leukemia; cancer cell; career; career development; chemotherapy; combinatorial; genetic profiling; genetic variant; improved; in vivo Model; insight; leukemia; leukemic transformation; leukemogenesis; member; mouse model; mutant; new therapeutic target; novel; novel therapeutic intervention; programs; protein expression; recombinase; research and development; response; single cell sequencing; skills; therapeutic target; tool; treatment response

Project Summary/Abstract Candidate: I am a postdoctoral fellow in the lab of Dr. Ross Levine in the Human Oncology & Pathogenesis Program at Memorial Sloan Kettering Cancer Center (MSKCC). My PhD studies allowed me to hone the technical and experimental skills required for interrogating clinically tractable molecular dependencies in cancer cells. My current research focuses on the generation of models of acute myeloid leukemia (AML) evolution to be used in the discovery of novel molecular dependencies and potential therapeutic targets. To that end, I have broadened my capabilities with CRISPR editing to generate an inducible AML model that allows for temporal control of mutagenesis and optimized a single cell DNA sequencing technique to evaluate the clonal framework of AML. My proposed research will build upon these initial studies to develop a new suite of sequential mutagenesis models of AML. These models developed in the K99 phase of this grant will serve as tools for the discovery of essential proteins/pathways for leukemic cells. My long-term career goal is to lead an independent research group focused on the identification and characterization of molecular dependencies of AML using precise models of disease evolution through sequential mutagenesis. To accomplish these goals, I have outlined a career plan that will 1) expand of my technical skills and scientific capacity, 2) improve my scientific communications with the field, 3) advance my supervisory and leadership abilities, 4) develop and foster collaborative relationships and 5) prepare me for the transition to independence. Project: Molecular profiling studies of AML patients infer a progressive acquisition of mutations that drives leukemogenesis, but are unable to delineate the dominant clonal framework leading to disease or identify the precise mutational order for certain genes, such as NPM1. Current models of AML are unable to truly recapitulate the step-wise mutagenesis observed in patients. Our single cell sequencing studies have further resolved the clonal structure of AML at single cell resolution and with these studies, I aim to generate new models that accurately depict the sequential mutagenesis of AML evolution. The specific aims are: 1) examine mechanisms of co-mutational clonal dominance and mutation order in AML patients using single cell profiling, 2) determine the impact of mutational acquisition on disease development and progression of NPM1-mutant AML, and 3) elucidate molecular dependencies of disease derived from mutant NPM1 and co-occurring mutations. Environment: The Levine lab is part of the MSKCC Molecular Cancer Medicine Service, Human Oncology & Pathogenesis Program (HOPP), for which Dr. Levine is Chief. The Levine lab is a core member of the Center for Hematologic Malignancies and the Center for Epigenetics Research, directed by Dr. Abdel-Wahab and Dr. Kristian Helin, respectively. These affiliations at MSKCC, a state-of-the-art institution, provide a rich set of collaborative, technical and scientific resources to perform the research and career development proposed here.

项目摘要/摘要 候选人：我是罗斯·莱文博士在人类肿瘤学和病理学实验室的博士后研究员 计划在纪念斯隆·凯特琳癌症中心(MSKCC)。我的博士学习使我能够磨练技术 以及询问癌细胞中临床上易处理的分子依赖性所需的实验技能。我的 目前的研究集中在急性髓系白血病(AML)进化模型的生成上，以用于 发现新的分子依赖性和潜在的治疗靶点。为此，我扩大了 我能够使用CRISPR编辑来生成可诱导的AML模型，该模型允许对 并对单细胞DNA测序技术进行了优化，以评估AML的克隆框架。 我提议的研究将建立在这些初步研究的基础上，以开发一套新的顺序突变 急性髓系白血病的模型。在这笔赠款的K99阶段开发的这些模型将用作发现 白血病细胞的必需蛋白质/途径。我的长期职业目标是领导一项独立研究 小组专注于使用精确模型识别和表征急性髓系白血病的分子依赖性 通过顺序突变实现的疾病进化。为了实现这些目标，我概述了一份职业规划 这将1)扩大我的技术技能和科学能力，2)改善我的科学交流 实地，3)提高我的监督和领导能力，4)发展和培养协作关系 5)为我向独立的过渡做好准备。 项目：对急性髓细胞白血病患者的分子图谱研究推断导致突变的渐进性获得 白血病发生，但无法描绘导致疾病的显性克隆框架或识别 某些基因的精确突变顺序，如NPM1。目前的AML模型无法真正概括 在患者身上观察到的逐步诱变。我们的单细胞测序研究进一步解决了 AML在单细胞分辨率下的克隆结构，通过这些研究，我的目标是产生新的模型 准确描绘了急性髓系白血病进化的顺序突变。具体目标是：1)审查机制 用单细胞图谱分析AML患者共突变克隆显性和突变顺序，2)确定 突变获取对NPM1突变AML疾病发生和进展的影响，以及3) 阐明来自突变NPM1和共生突变的疾病的分子相关性。 环境：莱文实验室隶属于MSKCC分子癌症医学服务，人类肿瘤学和 致病计划(HOPP)，莱文博士是该计划的负责人。莱文实验室是该中心的核心成员 血液恶性肿瘤和表观遗传学研究中心，由Abdel-Wahab博士和Dr。 分别是克里斯蒂安·海林。作为一家最先进的机构，MSKCC的这些从属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。