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.

项目摘要： 慢性脊髓细胞性白血病（CMML）是一种侵略性的髓样肿瘤 骨髓发育不良，细胞质，周围单核细胞增多症和急性髓性白血病阳性 （AML）转化。尽管均匀致命，但最初存在于临床无症状状态 并在不治疗的情况下进行数周到数月的监测。在所有患者中，CMML总是 发展为更有症状的疾病，或者经历AML转化。就是这样 致命的转化，导致CMML惨淡的预后和中位生存期34 月份。重要的是，进展的分子决定剂对此很少了解。 CMML病 进展和AML转化历史上与通用变化有关 建筑称为“克隆进化”。但是，很大一部分患者藏有相同的躯体 突变和变异等位基因频率在诊断时发展到该频率。我们的实验室有 发现了一种非共隆进化适应性，在这种适应中，白血病造血干细胞分化 在炎症的背景下，炎症性GMP导致适应性增加，同时保持 相同的体细胞突变曲目。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 炎症性侮辱引起与疾病紧密相关的白血病GMP的分化 进展。该假设将在以下特定目的中进行检验：（1）建立第一个前瞻性 CMML的纵向队列研究。通过回顾性捕获所有炎症伤害非常困难 临床分析。为了解决这个问题，这个目标将组装第一个多机构的前瞻性纵向 CMML的队列研究专门设计，以确定炎症性损伤是否与 疾病进展。其次，我们将利用本研究中的样品来验证大量基因表达 签名和基于流的测定法，以识别与炎症性GMP偏置状态的CMML病例。 最后，我们将利用经过处理过的CMML的回顾群体来确定现有疗法对 这个GMP有偏见。 （2）确定炎症GMP是否有偏见是进化 可以热利用的适应性。在此目标中，我们将使用一般的工程和 CMML的患者衍生模型以建立炎症GMP的克隆起源 能力以及早期治疗对这种细胞群的影响。