CORRELATIVE SCIENCE CORE

Core 3 的主要目标是为 SPORE 提供所需的基础设施和专业知识 对患者样本和异种移植人类开发、验证和实施分子生物标志物测试 白血病。这些测试将用于表征从患者身上获得的骨髓肿瘤的反应 以及每个项目中正在测试的靶向治疗的临床前模型。核心由 Jon C. 博士领导。 Aster 是一名高级白血病研究者和执业血液病理学家。测试将在核心中进行 包括测量 NPM1 和 DNMT3A 突变状态（项目 1）、SYK 激活（项目 2）、 编码剪接体成分和 SF3B1 抑制的基因的突变状态（项目 3），以及 免疫检查点蛋白的表达（项目 4）。该核心还将执行串行 NextGen 测序 确定靶向治疗对克隆动力学的影响，并开发新的测试来评估 肿瘤细胞对细胞凋亡的敏感性（BH3 分析/线粒体启动），或预测和衡量 肿瘤细胞对 SYK 抑制剂、Menin/MLL 抑制剂和其他靶向治疗的反应。 核心的具体目标是： 1) 要使用经过临床验证的基于扩增子的 NextGen 测序测试来识别突变，请定义 克隆异质性，并跟踪治疗期间骨髓肿瘤的克隆进化 2) 开发、验证和实施磷酸-SYK、免疫检查点蛋白、谱系-的测试 特定宿主免疫细胞标记物和其他蛋白质生物标记物 3) 开发、验证和实施基于 RNA 分析的测试，以识别有效的特征 使用剪接体等新型治疗剂靶向白血病信号通路 抑制剂和 Menin/MLL 抑制剂 4) 开发、验证和实施 BH3 分析/线粒体启动测定来预测 骨髓肿瘤对靶向治疗的反应

The major goals of Core 3 are to provide the SPORE with the infrastructure and professional expertise needed to develop, validate, and implement molecular biomarker tests on patient samples and xenografted human leukemias. These tests will be used to characterize the response of myeloid neoplasms obtained from patients and preclinical models to targeted therapies being tested in each of the projects. The Core is led by Dr. Jon C. Aster, a senior leukemia investigator and practicing hematopathologist. Tests will be carried out in the Core will include assays that gauge NPM1 and DNMT3A mutational status (Project 1), SYK activation (Project 2), mutational status of genes encoding spliceasome components and SF3B1 inhibition (Project 3), and the expression of immune checkpoint proteins (Project 4). The Core will also perform serial NextGen Sequencing to determine the effect of targeted therapy on clonal dynamics, and develop new tests that assess the sensitivity of tumor cells to apoptosis (BH3 profiling/mitochondrial priming), or that predict and gauge the response of neoplastic cells to SYK inhibitors, Menin/MLL inhibitors, and other targeted therapeutics. The specific aims of the Core are: 1) To use a clinically validated amplicon-based NextGen sequencing test to identify mutations, define clonal heterogeneity, and follow the clonal evolution of myeloid neoplasms during therapy 2) To develop, validate, and implement tests for phospho-SYK, immune checkpoint proteins, lineage- specific host immune cell markers, and other protein biomarkers 3) To develop, validate, and implement RNA profiling-based tests that identify signatures of effective targeting of leukemogenic signaling pathways with novel therapeutic agents, including spliceasome inhibitors, and Menin/MLL inhibitors 4) To develop, validate, and implement a BH3 profiling/mitochondrial priming assay to predict the response of myeloid neoplasms to targeted therapeutics