Project 1: Clonal Dynamics Guiding Curative Therapies for Acute Myeloid Leukemia

项目摘要/摘要 急性髓系白血病(AML)是一种致命性极强、控制不佳的疾病，可迅速转化为 完全缓解，但复发导致绝大多数患者死亡。该病的遗传进化 已经被追溯定义，但抵抗治疗的基础和克服它的有效策略 都是缺乏的。这个项目试图利用定义明确的小鼠模型，其中人类白血病基因 等位基因诱导高穿透性、致命性AML，可通过化疗暂时缓解 患者使用的药物。将这些基本生物学特征与新的量化策略相结合 评估克隆行为、克隆分子特征、物理定位和体内生长参数 随着时间的推移，途径、细胞周期和细胞凋亡将为数学建模提供多维数据集 与以下参数相关的参数：1.体内克隆优势(特定目标1)和2.对 体内化疗(特定目标2)。这些模型将指导实验测试的作用 疾病体内行为的参数，然后将被用来开发和测试方法 加强对急性髓细胞白血病的持久控制(具体目标3)。

Project Summary / Abstract Acute myeloid leukemia (AML) is rapidly fatal, poorly controlled disease that can be rapidly brought into complete remission but where relapse kills the vast majority of patients. The genetic evolution of the disease has been defined retrospectively, but the basis for resistance to therapy and effective strategies to overcome it are lacking. This project seeks to take advantage of well-defined mouse models where a human leukemogenic allele induces highly penetrant, lethal AML that can be temporarily brought into remission by chemotherapy agents used in patients. Combining these basic biologic features with novel strategies for quantitatively assessing clonal behavior, clonal molecular features, physical localization and the in vivo parameters of growth pathway, cell cycle and apoptosis over time will provide multidimensional datasets for mathematical modeling of the parameters correlating with: 1. Clonal dominance in vivo (Specific Aim 1) and, 2. Sensitivity/resistance to chemotherapy in vivo (Specific Aim 2). The models will guide experimental testing of the role of the parameters in the in vivo behavior of the disease that will then be used to develop and test methods for enhancing durable control of AML (Specific Aim 3).