CORRELATIVE SCIENCE CORE

核心3的主要目标是为孢子提供所需的基础设施和专业知识 开发、验证和实施对患者样本和异种移植人类的分子生物标记物测试 白血病。这些测试将被用来表征从患者那里获得的髓系肿瘤的反应。 以及在每个项目中正在测试的靶向治疗的临床前模型。核心由乔恩·C博士领导。 埃斯特说，他是一名资深白血病研究员，也是一名执业的血液病理学家。测试将在核心遗嘱中进行 包括检测NPM1和DNMT3A突变状态(项目1)、SYK激活(项目2) 编码剪接体组分的基因突变状态和SF3B1抑制(项目3)，以及 免疫检查点蛋白的表达(项目4)。核心还将执行序列下一代测序 为了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 肿瘤细胞对凋亡的敏感性(BH3图谱/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药物的反应。 核心的具体目标是： 1)要使用临床验证的基于扩增的NextGen测序测试来识别突变，请定义 克隆异质性，并在治疗过程中跟踪髓系肿瘤的克隆进化 2)开发、验证和实施磷酸化SYK、免疫检查点蛋白、谱系- 特定的宿主免疫细胞标志物和其他蛋白质生物标志物 3)开发、验证和实施基于RNA分析的测试，以识别有效的签名 用包括剪接体在内的新型治疗药物靶向白血病信号通路 抑制剂和梅宁/MLL抑制剂 4)开发、验证和实施BH3图谱/线粒体启动试验，以预测 髓系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