The impact of aging-associated chronic inflammation on the selection for oncogenic driver mutations in hematopoietic stem cells

项目摘要 衰老与癌症发病率的增加有关，包括血液癌症，如急性骨髓性白血病， 白血病许多白血病已经显示在造血干细胞（HSC）中起始，造血干细胞（HSC）是 负责在个体的一生中再生所有的血液谱系细胞。这使HSC处于 在疾病过程中尤其脆弱。HSC的正常运作需要平衡 维持HSC库的自我更新和产生造血细胞的分化之间的关系。这 平衡是HSC与其环境中的因素之间动态相互作用的结果，所有这些都显示出 随着年龄的增长，功能下降，因此可能导致功能障碍和疾病。一个这样 环境因素是炎症。衰老与低度慢性炎症有关， 与衰老有关的疾病，如癌症，与慢性炎症有关。此外，炎症可以 影响HSC自我更新和分化的平衡。该提案旨在建立以下联系： 相关发现：i）HSC及其微环境随年龄增长而下降，ii）炎症增加 随着年龄的增长，和iii）白血病发病率随着年龄的增长而增加。初步数据显示抑制衰老- 相关的炎症可防止HSC功能老化相关的下降。 我们的实验室提出了适应性肿瘤发生模型，这是一种进化模型，可以解释指数增长 癌症发病率随年龄增长而增加。我们认为，在一个年轻、健康的个体中，细胞和环境是 最佳拟合，使得改变表型的突变将改善适应性的机会低。这抑制 年轻人癌症的发展。但是随着年龄的增长微环境的变化， 例如组织损伤或炎症，会降低细胞及其周围组织的适应性， 增加改变表型的突变提供适应性益处的机会。这可能导致 携带突变的细胞扩增，从而推动白血病的发展。 这项提案将解决减少与衰老相关的慢性炎症是否可以预防衰老- 与HSC功能下降相关（目的1），衰老是否会导致致癌基因选择增加， HSC中的突变（Aim 2A），以及减少衰老相关的慢性炎症是否可以预防 由于年龄的致癌适应（目的2B）。这项研究的结果可以揭示预防艾滋病的新方法。 治疗白血病

PROJECT SUMMARY Aging is associated with an increased incidence of cancer, including blood cancers like acute myeloid leukemia. Many leukemias have been shown to initiate in the hematopoietic stem cell (HSC), which is responsible for regenerating all blood lineage cells over the life of an individual. This places the HSC at a particularly vulnerable position in disease processes. Proper functioning of the HSC requires a balance between self-renewal to maintain the HSC pool and differentiation to generate hematopoietic cells. This balance is a result of dynamic interactions between the HSC and factors in its environment, all of which display a functional decline with age, and thus can contribute to dysfunction and disease with age. One such environmental factor is inflammation. Aging is associated with low-grade, chronic inflammation, and many aging-associated diseases, like cancer, have been linked to chronic inflammation. Further, inflammation can impact the balance of HSC self-renewal and differentiation. This proposal aims to draw connections between the correlative findings that i) HSCs and their microenvironment decline with age, ii) inflammation increases with age, and iii) leukemia incidence increases with age. Preliminary data suggest that inhibiting aging- associated inflammation prevents aging-associated decline in HSC function. Our lab proposes the Adaptive Oncogenesis Model, an evolutionary model to explain the exponential increase in cancer incidence with age. We propose that in a young, healthy individual, cells and the environment are optimally fit, such that the chance a phenotype-altering mutation will improve fitness is low. This suppresses the development of cancer in young individuals. However, with age, perturbations in the microenvironment, such as tissue damage or inflammation, can decrease the fitness of cells and their surrounding tissue, thus increasing the chance that a phenotype-altering mutation will provide an adaptive benefit. This can result in expansion of cells carrying mutations and thus drive the development of leukemia. This proposal will address whether reducing aging-associated chronic inflammation can prevent aging- associated decline in HSC function (Aim 1), whether aging results in increased selection for oncogenic mutations in HSCs (Aim 2A), and whether reducing aging-associated chronic inflammation can prevent oncogenic adaptation due to age (Aim 2B). Findings from this research could uncover novel ways to prevent and treat leukemia.