Core D: Biomarker and Bio-Informatics Core

核心D -摘要 核心D的总体目标是提供以下相关生物标志物分析（包括生物信息学分析）： MPN-RC组织库中的原始标本，所有MPN-RC临床试验中的样本， 项目1-3和预期的组织库工作。核心D将进行体细胞基因组评估 来自组织库工作和基线治疗试验的所有MPN-RC样本的变化 以及响应时间评估。核心还将进行其他机制的动态分析- 基于生物标志物（如血清细胞因子，单细胞DNA和RNA测序研究，细胞遗传学， 组织病理学），其与项目1-3中的每项生物学和临床研究相关。使用基因组 分析将为项目1-3提供为生物学研究选择遗传注释样本的能力 旨在探讨体细胞突变与疾病发病机制的生物学特征之间的关系， 和治疗依赖性。该核心还将对基于机制的生物标志物进行动态分析 与项目1-4中的每项生物学和临床研究相关。这些试验的目的是提供 全面的遗传学和生物学相关研究以及帮助确定机械影响， 以及耗尽骨髓纤维化（MF）干细胞的能力，这些假设驱动的治疗干预。 所提出的分析将导致大量的整合基因组、基因表达和细胞因子数据 临床标注和同质治疗的患者。此外，项目4中提出的临床试验是 基于机械原理，源于项目1-3中的工作。相关的生物标志物测定直接 与将在项目4中研究的治疗剂的拟定作用机制相关。 这些研究将允许评估特定治疗干预的机制影响， 使我们能够证明新的治疗靶点和途径。此外，这将允许生物评估 治疗反应者和无反应者的差异，从而深入了解耐药机制。重要的是， 我们开发了严格的组织工具，以保持数据完整性、可追溯性和 再现性标准时，处理的数量和各种数据涉及的大规模 生物标志物分析。提供的最先进和新型生物标志物测定的整合 核心D，具有强大的临床前和临床研究将提供一个独特的机会，获得新的基因组和 MPN发病机制的生物学见解。

CORE D – Abstract The overall aim of Core D is to provide correlative biomarker analyses (including bioinformatics analysis) of primary specimens in the MPN-RC tissue bank, samples arising from all MPN-RC clinical trials, experiments in Projects 1-3, and prospective tissue banking efforts. Core D will carry out assessment of somatic genomic alterations on all MPN-RC samples derived from tissue banking efforts, and from therapeutic trials at baseline and the time of response assessment. The core will also carry out dynamic analyses of other mechanism- based biomarkers (such as serum cytokines, single-cell DNA and RNA sequencing studies, cytogenetics, and histopathology) which pertain to each of the biologic and clinical studies in Projects 1-3. The use of genomic profiling will provide Projects 1-3 with the ability to select genetically annotated samples for biologic studies aimed at investigating the relationship between somatic mutations, biological features of disease pathogenesis, and therapeutic dependencies. The core will also carry out dynamic analyses of mechanism-based biomarkers which pertain to each of the biologic and clinical studies in Projects 1-4. The goal of these assays is to provide comprehensive genetic and biologic correlative studies as well as to help determine the mechanistic impact, and the ability to deplete Myelofibrosis (MF) stem cells, of these hypothesis-driven therapeutic interventions. The proposed analyses will result in integrated genomic, gene expression, and cytokine data of a large number of clinically annotated and homogenously treated patients. As well, the clinical trials proposed in Project 4 are mechanistically based, and stem from work in Projects 1-3. The correlative biomarker assays are directly related to the proposed mechanisms of action of the therapeutic agents which will be investigated in Project 4. These studies will allow for an assessment of the mechanistic impact of specific therapeutic interventions and allow us to credential novel therapeutic targets and pathways. In addition, this will allow biological assessment of treatment responders and non-responders, thus giving insight into mechanisms of resistance. Importantly, we have developed rigorous organizational tools in order to maintain data integrity, traceability and reproducibility standards when dealing with the amount and the variety of data involved in the large-scale biomarker analyses for this core. The integration of state-of-the-art and novel biomarker assays offered by Core D, with robust preclinical and clinical studies will afford a unique opportunity to gain new genomic and biologic insights into MPN pathogenesis.