The impact of inflammation on HSPC composition and disease progression in chronic myelomonocytic leukemia

炎症对慢性粒单核细胞白血病HSPC组成和疾病进展的影响

• 批准号: 10607598
• 负责人: Eric Padron
• 金额: $ 63.61万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-07 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607598
• 关键词: Acceleration; Acute Myelocytic Leukemia; Address; Adult; Biological Assay; Bone Marrow; CD34 gene; Cells; Chronic; Chronic Myelomonocytic Leukemia; Classification; Clinical; Clinical Management; Clonal Evolution; Cytokine Network Pathway; Cytokine Receptors; Data; Diagnosis; Disease; Disease Progression; Dysplasia; Early treatment; Erythroid; Event; Gene Expression Profile; Gene Frequency; Gene Mutation; Genetic Engineering; Genetic Transcription; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Immunocompromised Host; Infection; Inflammation; Inflammatory; Institution; JAK1 gene; Knowledge; Laboratories; Leukemic Cell; Leukemic Hematopoietic Stem Cell; Literature; Longitudinal Studies; Longitudinal cohort; Longitudinal cohort study; Malignant - descriptor; Megakaryocytes; Modeling; Molecular; Monitor; Monocytosis; Myeloid Cells; Myeloid Leukemia; Myeloproliferative disease; Natural History; Nature; Non-Malignant; Pathologic; Patients; Peripheral; Phase I/II Clinical Trial; Phenotype; Population; Pre-Clinical Model; Process; Prognosis; Proliferating; Retrospective cohort; Sampling; Sampling Studies; Somatic Mutation; Stimulus; Stress; Subgroup; Systemic infection; Testing; Therapeutic; Time; adverse outcome; cytokine; cytopenia; design; disease natural history; fitness; follow-up; genetic architecture; genetic variant; granulocyte-monocyte progenitors; hematopoietic stem cell differentiation; inflammatory milieu; inhibitor; leukemia; leukemic transformation; monocyte; mortality; overexpression; patient subsets; peripheral blood; pre-clinical; prevent; progenitor; programs; prospective; response; self-renewal

Project Summary: Chronic Myelomonocytic Leukemia (CMML) is an aggressive myeloid neoplasm hallmarked by bone marrow dysplasia, cytopenias, peripheral monocytosis, and a propensity for Acute Myeloid Leukemia (AML) transformation. Although uniformly fatal, CMML initially present in a clinically asymptomatic state and is monitored, without treatment, for a period of weeks to months. In all patients, CMML invariably progresses to either a more symptomatic version of disease or undergoes AML transformation. It is this lethal transformation that is responsible for CMML's dismal prognosis and median survival of only 34 months. Importantly, the molecular determinants of progression are poorly understood. CMML disease progression and AML transformation have been historically associated with changes in genetic architecture termed “clonal evolution.” However, a large subset of patients harbor the same somatic mutations and variant allele frequency at the time of progression to that at diagnosis. Our laboratory has discovered a non-clonal evolutionary adaptation whereby leukemic hematopoietic stem cells differentiate to inflammatory GMPs leading to increased fitness in the context of inflammation while maintaining the same repertoire of somatic mutations. Further, this adaptation was associated with adverse outcomes in a retrospective cohort of CMML patients. Last, preclinical inflammatory models of CMML were able to recapitulate this evolutionary adaptation in our preliminary data. Therefore, we hypothesize that inflammatory insults induce the differentiation of leukemic GMPs that are tightly associated with disease progression. This hypothesis will be tested in the following specific aims: (1) Establish the first prospective longitudinal cohort study in CMML. It is very difficult to capture all inflammatory insults via retrospective clinical analysis. To address this, this aim will assemble the first multi-institution prospective longitudinal cohort study of CMML specifically designed to determine whether inflammatory insults are associated with disease progression. Second, we will utilize samples from this study to validate bulk gene expression signatures and a flow-based assay to identify those CMML cases with and inflammatory GMP biased state. Last, we will leverage retrospective cohorts of treated CMML to determine the impact of existing therapy on this GMP biased state. (2) Determine whether the inflammatory GMP biased state is an evolutionary adaptation that can be therapeutically exploited. In this aim, we will use both genetically engineered and patient derived models of CMML to establish the clonal origin of inflammatory GMP, there self-renewing capacity, and the impact of early therapy on this population of cells.

项目概要： 慢性粒单核细胞白血病 (CMML) 是一种以骨为特征的侵袭性骨髓肿瘤 骨髓发育不良、血细胞减少、外周血单核细胞增多和急性髓系白血病倾向 (AML) 转化虽然都是致命的，但 CMML 最初呈临床无症状状态。 并在不进行治疗的情况下对所有患者进行为期数周至数月的监测。 进展为更有症状的疾病或经历 AML 转化。 导致 CMML 预后不佳且中位生存期仅为 34 的致命转化 重要的是，人们对 CMML 疾病进展的分子决定因素知之甚少。 历史上，进展和 AML 转化与遗传变化有关 被称为“克隆进化”的架构。然而，很大一部分患者拥有相同的体细胞。 我们的实验室有从进展到诊断时的突变和变异等位基因频率。 发现白血病造血干细胞分化的非克隆进化适应 炎症 GMP 导致炎症环境下的适应性增强，同时保持 此外，这种适应与不良后果相关。 CMML 患者的回顾性队列最后，CMML 的临床前炎症模型能够 因此，我们在我们的初步数据中概括了这种进化适应。 炎症损伤诱导与疾病密切相关的白血病 GMP 的分化 该假设将在以下具体目标中进行测试：（1）建立第一个前瞻性 CMML 的纵向队列研究很难通过回顾性捕获所有炎症损伤。 为了解决这个问题，该目标将汇集第一个多机构前瞻性纵向分析。 CMML 队列研究专门设计用于确定炎症损伤是否与 其次，我们将利用本研究的样本来验证大量基因表达。 特征和基于流的测定来识别那些具有炎症 GMP 偏向状态的 CMML 病例。 最后，我们将利用治疗 CMML 的回顾性队列来确定现有疗法对 (2) 确定炎症性GMP偏向状态是否是一种进化状态 为了实现这一目标，我们将使用基因工程技术和技术。 患者衍生的CMML模型建立炎症GMP的克隆起源，有自我更新能力 能力，以及早期治疗对该细胞群的影响。