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：我是人类肿瘤和发病机理罗斯·莱文博士实验室的博士后研究员 纪念斯隆·凯特林癌症中心（MSKCC）的计划。我的博士研究使我能够磨练技术 以及询问癌细胞中临床上可探讨的分子依赖性所需的实验技能。我的 当前的研究重点是用于用于用于用于用于 发现新的分子依赖性和潜在的治疗靶标。为此，我扩大了 我的CRISPR编辑功能以生成可诱导的AML模型，该模型允许时间控制 诱变并优化了单个细胞DNA测序技术，以评估AML的克隆框架。 我提出的研究将基于这些最初的研究，以开发新的顺序诱变套件 AML的模型。这些在本赠款的K99阶段开发的模型将作为发现的工具 白血病细胞的必需蛋白质/途径。我的长期职业目标是领导独立研究 专注于使用精确模型的分子依赖性鉴定和表征 通过顺序诱变的疾病进化。为了实现这些目标，我概述了职业计划 1）扩大我的技术技能和科学能力，2）改善我与 该领域，3）提高我的监督和领导能力，4）建立和建立合作关系 5）我为过渡到独立做好准备。 项目：AML患者的分子分析研究推断出驱动的突变 白血病发生，但无法描绘出主要的克隆框架，导致疾病或确定 某些基因的精确突变顺序，例如NPM1。当前的AML模型无法真正概括 在患者中观察到的逐步诱变。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，我旨在生成新模型 准确地描述了AML进化的顺序诱变。具体目的是：1）检查机制 使用单细胞分析的AML患者的共裂克隆优势和突变顺序的 突变获取对NPM1突变AML疾病发展和进展的影响，3） 阐明源自突变NPM1和同时发生突变的疾病的分子依赖性。 环境：Levine Lab是MSKCC分子癌医学服务，人类肿瘤学和 发病机理计划（HOPP），莱文博士担任该计划。 Levine Lab是该中心的核心成员 血液学恶性肿瘤和表观遗传学研究中心，由Abdel-Wahab博士和博士指导 克里斯蒂安·海林（Kristian Helin）。这些隶属关系是在最先进的机构MSKCC提供的，提供了丰富的一套 在这里提出的研究和职业发展的协作，技术和科学资源。