Determining how aging-associated changes in the microenvironment contribute to leukemogenesis

确定与衰老相关的微环境变化如何导致白血病发生

• 批准号: 10176352
• 负责人: James V Degregori
• 金额: $ 43.92万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176352
• 关键词: Acute Myelocytic Leukemia; Age; Aging; B-Lymphocytes; Bone Marrow; Cell Aging; Cell Compartmentation; Cells; Clone Cells; Development; Directed Molecular Evolution; Disease; Elderly; Environment; Epigenetic Process; Event; Evolution; Funding; Gene Expression; Generations; Genetic; Genotype; Goals; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Impairment; Incidence; Inflammation; Inflammatory; Intervention; Life; Link; Malignant - descriptor; Malignant Neoplasms; Modeling; Modification; Multipotent Stem Cells; Mutation; Natural Selections; Oncogenic; Organ; Pharmacology; Phenotype; Population; Prevention; Risk; Role; Signal Transduction; Somatic Cell; Testing; Time; Tissues; age related; aged; cancer risk; carcinogenicity; environmental change; fitness; human old age (65+); improved; insight; leukemia; leukemogenesis; mouse model; mutant; prevent; reproductive success; senescence; stem; stem cells; therapy development; tumorigenesis

The risk of most cancers, including leukemias, increases exponentially as we age, with over 90% of cancers occurring after the age of 50. This association has been primarily ascribed to the gradual accumulation of mutations throughout life. We contend that the contribution of mutations (while necessary) is not sufficient to explain the role of aging in the development of leukemias and other cancers. Just as species evolution has been driven by environmental changes that select for adaptive phenotypes in populations, we propose that the changes in our tissues known to occur in old age are substantial contributors to oncogenesis. Inflammation and senescent cells increase in the bone marrow of the elderly, which along with other changes contribute to impaired hematopoiesis. In the current funding period, we have used mouse models to show that the aged and inflammatory bone marrow microenvironment reduces the fitness of B- cell progenitors, promoting selection for particular adaptive oncogenic events, leading to increased leukemogenesis in these contexts. Here, we will explore how changes in hematopoietic stem and early progenitor cell (HSPC) pools driven by microenvironmental alterations in old age influence selection on oncogenic events known to initiate acute myeloid leukemias. We will also develop interventions to reduce microenvironmental perturbations and associated oncogenesis in old age. Our central hypothesis is that aging-dependent increases in inflammation and senescent cells are critical for enhancing selection for oncogenic mutations that occur throughout life, and that dampening inflammation and/or removing senescent cells can reduce the risk of the associated leukemias. To test our hypothesis, we will pursue two aims: 1) Determine how aging, inflammation and senescence influence oncogenic adaptation in the HSPC compartment and 2) Identify the mechanisms underlying increased oncogenesis in aged HSPC pools. By determining whether and how microenvironmental changes impact HSPC fitness and thus oncogenic adaptation in old age, these results could provide a new explanation for links between aging and leukemia risk. In all, proposed studies could provide answers for fundamental questions: Why do we get more leukemias as we age? Why are particular oncogenic mutations selected for in the bone marrow of the elderly? Can we alter aging-associated positive selection for oncogenic events and thus reduce leukemia risk? These studies could suggest interventions that can reduce the risk of hematopoietic malignancies of old age by manipulating specific factors in the bone marrow microenvironment.

随着年龄的增长，大多数癌症（包括白血病）的风险呈指数级增加， 超过 90% 的癌症发生在 50 岁之后。这种关联主要归因于 突变在一生中逐渐积累。我们认为，贡献 突变（虽然必要）不足以解释衰老在发育中的作用 白血病和其他癌症。正如物种进化是由环境驱动的一样 选择群体中适应性表型的变化，我们建议我们的变化 已知老年时出现的组织是肿瘤发生的重要贡献者。炎症和 老年人骨髓中的衰老细胞增加，并伴有其他变化 导致造血功能受损。在当前资助期间，我们使用了小鼠模型 表明衰老和炎症的骨髓微环境降低了 B- 的适应性 细胞祖细胞，促进对特定适应性致癌事件的选择，导致 在这些情况下白血病发生增加。在这里，我们将探讨造血功能如何发生变化。 老年微环境变化驱动的干细胞和早期祖细胞（HSPC）库 影响对已知引发急性髓系白血病的致癌事件的选择。我们还将 制定干预措施以减少微环境扰动和相关的肿瘤发生 在年老时。我们的中心假设是，炎症和衰老相关的增加 衰老细胞对于增强对整个过程中发生的致癌突变的选择至关重要 抑制炎症和/或去除衰老细胞可以降低罹患癌症的风险 相关白血病。为了检验我们的假设，我们将追求两个目标：1）确定衰老的方式， 炎症和衰老影响 HSPC 区室的致癌适应，2) 确定老化 HSPC 池中肿瘤发生增加的机制。 通过确定微环境变化是否以及如何影响 HSPC 适应性和 因此，老年时的致癌适应，这些结果可以为链接提供新的解释 衰老与白血病风险之间。总而言之，拟议的研究可以为基本问题提供答案 问题：为什么随着年龄的增长，我们会患上更多的白血病？为什么特定的致癌突变 是为老年人的骨髓选择的吗？我们可以改变与衰老相关的积极选择吗 致癌事件从而降低白血病风险？这些研究可能会建议干预措施 可以通过操纵特定因素来降低老年造血系统恶性肿瘤的风险 在骨髓微环境中。