Aged tissue environments as drivers of oncogenic adaptation in hematopoiesis

老化的组织环境是造血过程中致癌适应的驱动因素

• 批准号: 10319990
• 负责人: James V Degregori
• 金额: $ 25.02万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319990
• 关键词: Age; Aging; Automobile Driving; B-Lymphocytes; Blood; Bone Marrow; CCAAT-Enhancer-Binding Protein-alpha; Cell Compartmentation; Cell Differentiation process; Cells; Development; Directed Molecular Evolution; Disease; Elderly; Environment; Epigenetic Process; Equilibrium; Event; Evolution; Gene Expression; Genetic; Goals; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Impairment; Incidence; Inflammation; Inflammatory; Intervention; Lead; Life; Link; Malignant Neoplasms; Modeling; Modification; Mutate; Mutation; Natural Selections; Oncogenic; Organ Model; Pharmacology; Phenotype; Population; Prevention; Process; Risk; Role; Signal Transduction; Somatic Cell; Testing; Time; Tissues; age related; aged; aging population; bone aging; cancer cell; cancer risk; carcinogenicity; environmental change; fitness; healthspan; hematopoietic hierarchy; human old age (65+); improved; leukemia; leukemogenesis; mouse model; mutant; prevent; self-renewal; stem; stem cells; success; therapy development; tumor microenvironment; 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 oncogenic 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 occurring in old age are substantial contributors to oncogenesis. In particular, inflammation increases in the bone marrow of the elderly, which contributes to impaired hematopoiesis. Our central hypothesis is that aging-dependent increases in inflammation are critical for enhancing selection for oncogenic mutations, and that dampening inflammation can reduce the risk of the associated leukemias. We previously 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. Here, we will explore how microenvironmental alterations in old age promote oncogenesis in immature hematopoietic stem and early progenitor cell (HSPC) pools at the apex of the hematopoietic hierarchy. We propose that C/EBPα and Myc activities are key hubs for oncogenic selection in aged bone marrow microenvironments due to their critical roles in balancing HSPC differentiation and self-renewal. Thus, we will develop interventions to reduce microenvironmental perturbations that deregulate C/EBPα and Myc and lead to oncogenesis in old age. To test our hypothesis, we will pursue two aims: 1) Determine whether aging and inflammation drive oncogenic adaptation in the HSPC compartment and 2) Identify mechanisms underlying increased oncogenesis with aging in 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, our 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 also identify interventions that reduce the risk of hematopoietic malignancies of old age by manipulating inflammatory factors that promote oncogenesis in the bone marrow microenvironment.

随着年龄的增长，患大多数癌症（包括白血病）的风险呈指数级增长