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）是一种侵袭性骨髓肿瘤， 骨髓发育不良、血细胞减少、外周单核细胞增多和急性髓性白血病倾向 (AML)转型虽然CMML是一致致命的，但最初临床上无症状 并在不治疗的情况下被监测数周至数月的时间。在所有患者中，CMML总是 进展为症状更明显的疾病或经历AML转化。正是这种 这种致命的转化导致CMML的预后很差，平均存活率只有34 个月重要的是，进展的分子决定因素知之甚少。CMML病 在历史上，进展和AML转化与遗传学改变有关。 这就是所谓的克隆进化然而，很大一部分患者具有相同的躯体疾病， 突变和变异等位基因频率在发展到诊断时。本实验室 发现了一种非克隆进化适应， 导致在炎症背景下健身增加，同时保持 相同的体细胞突变此外，这种适应与不良结果有关， CMML患者的回顾性队列。最后，CMML的临床前炎症模型能够 在我们的初步数据中概括了这种进化适应。因此，我们假设 炎性损伤诱导与疾病密切相关的白血病GMP的分化 进展这一假设将在以下具体目标进行检验：（1）建立第一个前瞻性的 CMML纵向队列研究。很难通过回顾来捕捉所有的煽动性侮辱， 临床分析为了解决这个问题，这一目标将汇集第一个多机构前瞻性纵向 CMML的队列研究，专门设计用于确定炎症损伤是否与 疾病进展。其次，我们将利用本研究的样本来验证批量基因表达 特征和基于流动的测定来鉴定具有炎性GMP偏向状态的那些CMML病例。 最后，我们将利用治疗的CMML的回顾性队列，以确定现有治疗对CMML的影响。 这种GMP偏见的状态。(2)确定炎症性GMP偏向状态是否是一种进化 可以被治疗利用的适应。在这个目标中，我们将使用基因工程和 患者来源的CMML模型，以建立炎性GMP的克隆起源， 能力，以及早期治疗对这一细胞群体的影响。