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

衰老相关慢性炎症对造血干细胞致癌驱动突变选择的影响

• 批准号: 9190098
• 负责人: Kelly Chiemi Higa
• 金额: $ 3.09万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9190098
• 关键词: Acute Myelocytic Leukemia; Address; Age; Aging; Anti-Inflammatory Agents; Anti-inflammatory; Biological Assay; Blood; Bone Marrow; Bone Marrow Transplantation; Cell Count; Cell Lineage; Cell physiology; Cells; Chronic; Clonal Expansion; Data; Development; Disease; Environment; Environmental Risk Factor; Equilibrium; Functional disorder; Health; Hematologic Neoplasms; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Incidence; Individual; Inflammation; Interleukins; Lead; Life; Link; Malignant Neoplasms; Modeling; Mus; Mutation; Natural regeneration; Oncogenes; Oncogenic; Phenotype; Positioning Attribute; Process; Property; Relapse; Research; Stem Cell Factor; Tissues; Transgenic Mice; Transplantation; actionable mutation; age related; aged; base; cancer cell; cytokine; fitness; functional decline; improved; leukemia; mouse model; novel; pressure; prevent; reconstitution; self-renewal; therapeutic target; tumorigenesis

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.

项目总结 衰老与癌症发病率的增加有关，包括急性髓系白血病等血癌。 白血病。许多白血病被证明起源于造血干细胞(HSC)，这是 负责在一个人的一生中再生所有的血统细胞。这将使HSC处于 在疾病过程中处于特别脆弱的地位。HSC的正常运作需要平衡 在自我更新以维持HSC库和分化以产生造血细胞之间。这 平衡是HSC与其环境中的因素之间动态相互作用的结果，所有这些都表现为 功能随着年龄的增长而下降，因此会随着年龄的增长而导致功能障碍和疾病。这样的一个 环境因素是炎症。衰老与低级别、慢性炎症和许多 与衰老相关的疾病，如癌症，被认为与慢性炎症有关。此外，炎症可以 影响HSC自我更新与分化的平衡。这项提议旨在找出 相关研究发现：1)HSCs及其微环境随增龄而下降，2)炎症加重 3)白血病发病率随年龄增长而增加。初步数据表明，抑制衰老-- 相关的炎症可以防止与衰老相关的HSC功能下降。 我们的实验室提出了适应性肿瘤发生模型，这是一种解释指数增长的进化模型 癌症发病率随年龄增长。我们认为，在一个年轻、健康的个体中，细胞和环境 最佳适合度，因此，表型改变突变改善适合度的机会很低。这抑制了 癌症在年轻人中的发展。然而，随着年龄的增长，微环境的扰动， 例如组织损伤或炎症，会降低细胞及其周围组织的适合性，因此 增加表型改变突变提供适应性益处的机会。这可能会导致 携带突变的细胞的扩张，从而推动白血病的发展。 这项提案将讨论减少与衰老相关的慢性炎症是否可以防止衰老- HSC功能相关下降(目标1)，衰老是否导致致癌选择增加 HSCs的突变(Aim 2A)，以及减少衰老相关的慢性炎症是否可以预防 年龄所致的致癌适应(目标2B)。这项研究的发现可能会发现预防 治疗白血病。