Effect of inflammation on JAK2 mutant evolution in the hematopoietic system: mathematical models and experiments

炎症对造血系统 JAK2 突变体进化的影响：数学模型和实验

• 批准号: 10630923
• 负责人: Angela Goffredo Fleischman
• 金额: $ 53.4万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-30 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630923
• 关键词: Acceleration; Acute; Acute Myelocytic Leukemia; Aspirin; Benign; Biological Assay; Biological Models; Blood coagulation; Cell Lineage; Cells; Chronic; Clinical; Clinical Trials; Collaborations; Complex; Computing Methodologies; Cues; Data; Development; Disease; Disease Progression; Dose; Early treatment; Evolution; Future; Goals; Growth; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Homeostasis; Inflammation; Inflammatory; Intervention; JAK2 gene; Kinetics; Laboratories; Mathematics; Measures; Mediating; Modality; Modeling; Mus; Mutation; Myelofibrosis; Myelogenous; Myeloproliferative disease; Outcome; Patients; Pharmaceutical Preparations; Population; Process; Production; Publishing; Research; Risk; Risk Reduction; Sampling; Schedule; Stimulus; Survival Rate; Testing; Therapeutic; Therapeutic Intervention; Translating; Treatment Protocols; Work; alternative treatment; cell type; design; drug discovery; effective therapy; experimental study; improved outcome; in silico; in vivo; inhibitor; mathematical model; mouse model; mutant; new therapeutic target; novel; novel therapeutics; predictive modeling; pressure; response; symptom management; targeted treatment; therapeutic evaluation; therapeutic target; treatment strategy

PROJECT SUMMARY/ABSTRACT Myeloproliferative neoplasm (MPN) is a hematologic malignancy characterized by the clonal outgrowth of hematopoietic cells with a somatically acquired mutation most commonly in JAK2 (JAK2V617F), which leads to excessive production of myeloid lineage cells. Patients with early stage MPN can spontaneously progress to myelofibrosis, a more aggressive stage of the disease with an average survival rate of two years. Moreover, MPN patients have a significant risk of developing acute myeloid leukemia (AML). The traditional approach to therapy in MPN is simply to reduce the risk of blood clots with aspirin, manage symptoms, and observe for progression of the disease. Therapeutic intervention is focused on patients with late stage disease, mostly due to the lack of currently available therapies that halt progression. There is thus a need for interventions that impact disease progression in MPN. Preliminary work by the laboratory of Dr. Fleischman, in collaboration with mathematical modelers Komarova and Wodarz, has shown that inflammation can accelerate the growth rate of JAK2V617F mutant cells relative to JAK2WT cells, and that this can potentially have a variety of consequences for the evolution of mutant cells at homeostasis. This suggests the possibility of a new treatment modality for early stage MPN, in which the evolutionary fate of the JAK2V617F mutants is altered and disease progression is delayed or halted. The overall goal of this proposal is to investigate how this can be achieved. In Aim 1, experiments are proposed that document the dynamics of JAK2WT and JAK2V617F mutant cells in isolation with and without inflammation for the purposes of model construction and parameterization. We will also interrogate the intracellular mechanisms responsible for the differential response of JAK2V617F mutants to inflammation. In Aim 2 we will perform experiments in which JAK2WT and JAK2V617F mutant cells are combined in mouse models with and without inflammation. This will quantify how the number of mutants influence the kinetic parameters of wild- type cells, which is important because we know that mutants themselves can increase inflammation and hence alter the dynamics. In Aim 3 we will measure how a panel of existing drugs impact the kinetic parameters of cells and use our model to predict combinations and dosing schedules that will lead to diminution of the mutant cells. Many treatment scenarios (in sequence and in combination) will be explored, and the most promising therapeutic approaches predicted by the model will be tested experimentally. This can identify better and currently unknown ways in which to utilize existing drugs. On a more exploratory level, the validated mathematical model can suggest which parameter(s) to target in which ways to make treatment more efficient than can be currently done. This information would facilitate development of future treatments and guide drug discovery and could be translated into a future clinical trial.

项目摘要/摘要 骨髓增生性肿瘤（MPN）是一种血液系统恶性肿瘤，其特征是 具有最常见于JAK 2（JAK 2 V617 F）的体细胞获得性突变的造血细胞，其导致 髓系细胞的过度产生。早期MPN患者可自发进展为 骨髓纤维化，这是疾病的一个更具侵略性的阶段，平均生存率为两年。此外，委员会认为， MPN患者有发生急性髓性白血病（AML）的显著风险。的传统方法 MPN的治疗只是用阿司匹林降低血栓的风险，控制症状，并观察 疾病的进展。治疗性干预集中在晚期疾病患者，主要是由于 目前缺乏有效的治疗方法来阻止疾病的发展。因此，需要采取干预措施， MPN中的疾病进展。Fleischman博士的实验室与 数学建模者Komarova和Wodarz已经表明，炎症可以加速肿瘤的生长速度， JAK 2 V617 F突变细胞相对于JAK 2 WT细胞的生长，并且这可能对JAK 2 V617 F突变细胞的生长产生各种后果。 突变细胞在体内平衡状态下的进化这表明了一种新的治疗方式的可能性， 阶段MPN，其中JAK 2 V617 F突变体的进化命运被改变并且疾病进展被延迟 或停止。本提案的总体目标是研究如何实现这一点。目标1： 提出记录JAK 2 WT和JAK 2 V617 F突变细胞在单独存在和不存在 炎症用于模型构建和参数化的目的。我们还将审问 JAK 2 V617 F突变体对炎症的差异反应的细胞内机制。在Aim中 2我们将进行实验，其中JAK 2 WT和JAK 2 V617 F突变体细胞在小鼠模型中组合， 并且没有炎症。这将量化突变体的数量如何影响野生型的动力学参数。 这一点很重要，因为我们知道突变体本身可以增加炎症， 改变动态。在目标3中，我们将测量一组现有药物如何影响细胞的动力学参数 并使用我们的模型来预测将导致突变细胞减少的组合和给药方案。 许多治疗方案（顺序和组合）将被探索，最有前途的治疗方案将是： 模型预测的方法将通过实验进行检验。这可以更好地识别目前未知的 如何利用现有的药物。在更探索性的层面上，经验证的数学模型可以 建议哪些参数以何种方式为目标，以使治疗比目前更有效。 这些信息将促进未来治疗的发展，并指导药物发现， 转化为未来的临床试验