The Contribution ofInfection to Preleukemic Clonal Hematopoiesis

项目总结/摘要 感染增加了癌症的风险，但这种联系的病理生理基础仍然很差 明白我们的长期目标是通过以下方法确定分子机制来改善癌症预防： 哪些感染会导致癌症我们选择研究血液是为了利用现有的工具， 造血干细胞（HSC）和血癌领域的知识。我们之前的工作已经确定 感染期间释放的炎症信号对静止的HSC施加强大的激活压力， 诱导它们分化和分化。持续的炎症应激导致HSC衰竭。值得注意的是， HSC不是一个同质的群体，并且炎症信号耗尽了HSC的反应性亚群 比其他人更快。在急性髓细胞性白血病（AML）的情况下，散发性创始人突变具有 这些定义了具有不同白血病转化倾向的HSC亚群。 肿瘤抑制基因DNA甲基转移酶3A（DNMT 3A）的突变是最常见的创始者。 AML中的突变和鼠Dnmt 3a中的类似突变已显示损害分化， 加强自我更新。在人类中，DNMT 3A突变克隆在骨髓中扩增，导致克隆性的 65岁以上的人中有10%的人有造血功能。DNMT 3A突变型克隆性造血 与白血病转化的风险增加有关。使用创新的马赛克动物模型，我们 发现慢性感染加速了WT小鼠中Dnmt 3a突变型白血病前克隆的扩增， 是正常速度的三倍。因此，我们假设感染加速了白血病前期细胞的扩散， 通过诱导WT HSC的终末分化，从而提供选择Dnmt 3a突变型HSC的方法。 突变克隆的优势。在目标1中，我们将确定哪些炎症信号和哪些类型的炎症信号。 在我们的嵌合体动物模型中，感染促进Dnmt 3a突变型HSC扩增。在目标2中，我们将确定 Dnmt 3a突变体和WT HSC之间在细胞分裂、细胞死亡或分化方面的差异 解释了突变克隆的扩张。我们将利用这些发现来优化一个数学模型， 可用于预测这些因素的变化对白血病前期克隆扩增的影响。最后，在Aim 我们将使用功能获得和功能丧失研究来鉴定Dnmt 3a突变HSC的分子驱动因子。 在从先前的转录组筛选中选择的候选物中扩增。这些研究的总体影响 它们将揭示感染在白血病前克隆性白血病中作用的基本机制信息。 扩展，将成为未来工作的基础，设计特定的治疗干预措施，以预防癌症 出现。

Project Summary / Abstract Infections increase the risk of cancer; yet the pathophysiologic basis for this association remains poorly understood. Our long term goal is to improve cancer prevention by defining the molecular mechanisms by which infections promote cancer. We have chosen to study blood in order to capitalize on existing tools and knowledge in the field of hematopoietic stem cells (HSCs) and blood cancers. Our prior work has established that inflammatory signals released during infection exert strong activation pressure on quiescent HSCs, inducing them to divide and differentiate. Persistent inflammatory stress leads to HSC exhaustion. Notably, HSCs are not a homogeneous population, and inflammatory signals exhaust responsive subsets of HSCs more quickly than others. In the case of acute myelogenous leukemia (AML), sporadic founder mutations have been identified and these define HSC subpopulations with varying propensity for leukemic transformation. Mutations in the tumor suppressor DNA methyltransferase 3A (DNMT3A) are the most common founder mutation in AML, and analogous mutations in murine Dnmt3a have been shown to impair differentiation while enhancing self-renewal. In humans, DNMT3A-mutant clones expand in the marrow, leading to clonal hematopoiesis in up to 10% of all people over the age of 65. DNMT3A-mutant clonal hematopoiesis is associated with an increased risk of leukemic transformation. Using an innovative mosaic animal model, we find that chronic infection accelerates the expansion of Dnmt3a-mutant preleukemic clones in a WT mouse to three times the normal rate. We therefore hypothesize that infection accelerates the expansion of preleukemic Dnmt3a-mutant HSCs by inducing terminal differentiation of WT HSCs, thereby providing a selection advantage for the mutant clones. In Aim 1 we will ascertain what inflammatory signals and what types of infections promote Dnmt3a-mutant HSC expansion in our mosaic animal model. In Aim 2 we will determine whether differences between Dnmt3a-mutant and WT HSCs in cell division, cell death, or differentiation account for expansion of the mutant clone. We will use these findings to optimize a mathematical model that can be used to predict the effects of changes in those factors on preleukemic clonal expansion. Finally, in Aim 3 we will use gain-of-function and loss-of-function studies to identify molecular drivers of Dnmt3a-mutant HSC expansion among candidates selected from prior transcriptome screening. The overall impact of these studies is that they will reveal essential mechanistic information about the role of infections in preleukemic clonal expansion that will form the basis for future work to design specific therapeutic interventions to prevent cancer emergence.