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

项目总结： 慢性粒单核细胞白血病(CMML)是一种以骨骼为特征的侵袭性髓系肿瘤 骨髓发育不良、细胞减少、外周血单核细胞增多和急性髓系白血病的倾向 (AML)转换。尽管CMML都是致命的，但最初表现为临床无症状状态。 并且在没有治疗的情况下被监测数周至数月。在所有患者中，CMML总是 要么进展到更有症状的疾病版本，要么经历AML转化。就是这个 致命性转化导致CMML预后惨淡，中位存活率仅为34 月份。重要的是，人们对进展的分子决定因素知之甚少。CMML病 进展性和急性髓系白血病的转化历来与基因的变化有关 建筑被称为“克隆进化”。然而，有很大一部分患者拥有相同的体细胞 疾病进展到确诊时的突变和变异等位基因频率。我们的实验室有 发现了白血病造血干细胞分化的非克隆性进化适应 炎症性GMP导致在炎症背景下增加适应性，同时保持 相同的体细胞突变谱系。此外，这种适应与#年的不良后果有关。 一组CMML患者的回顾性队列研究。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 炎性侮辱诱导与疾病密切相关的白血病GMP分化 进步。这一假设将在以下具体目标中得到检验：(1)建立第一个预期 CMML的纵向队列研究。通过回顾很难捕捉到所有的煽动性侮辱 临床分析。为了解决这一问题，这一目标将汇集第一个多机构预期纵向 针对CMML的队列研究，旨在确定炎性侮辱是否与 疾病的发展。其次，我们将利用这项研究的样本来验证批量基因表达 签名和基于流动的分析，以识别那些具有炎症性GMP偏向状态的CMML病例。 最后，我们将利用接受治疗的CMML的回顾队列来确定现有治疗方法对 这种GMP偏向的状态。(2)确定炎症性GMP偏向状态是否为进化状态 可以在治疗上利用的适应。在这个目标中，我们将使用基因工程和 患者衍生的CMML模型建立炎性GMP的克隆性起源，存在自我更新 能力，以及早期治疗对这群细胞的影响。

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.