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

大多数癌症的风险，包括白血病，随着年龄的增长呈指数级增加， 超过90%的癌症发生在50岁以后。这种联系主要被归因于 导致突变在整个生命中逐渐积累。我们争辩说， 突变(尽管是必要的)不足以解释衰老在糖尿病发展中的作用 白血病和其他癌症。就像物种进化是由环境驱动的一样 在种群中选择适应性表型的变化，我们认为我们的 已知发生在老年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多，伴随着其他变化 会导致造血功能受损。在当前的资助期内，我们使用了鼠标模型 说明衰老和炎症的骨髓微环境降低了B细胞的适合性。 细胞前体，促进对特定适应性致癌事件的选择，导致 在这些情况下增加了白血病的发生。在这里，我们将探索造血细胞的变化 老年微环境变化驱动的干细胞池和早期祖细胞(HSPC)池 影响已知的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 垂暮之年。我们的中心假设是，依赖于衰老的炎症和 衰老细胞对于增强全程发生的致癌突变的选择至关重要。 抗炎和/或清除衰老细胞可以降低罹患 伴发白血病。为了验证我们的假设，我们将追求两个目标：1)确定衰老如何， 炎症和衰老影响HSPC室的致癌适应2) 确定在高龄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适合性和 因此，老年的致癌适应，这些结果可能为联系提供新的解释 衰老和白血病风险之间的关系。总而言之，拟议中的研究可以为基础研究提供答案 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 在老年人的骨髓中挑选？我们能改变与衰老相关的积极选择吗？ 对于致癌事件，从而降低白血病风险？这些研究可能建议采取干预措施 这可以通过操纵特定的因素来降低老年血液系统恶性肿瘤的风险 在骨髓微环境中。

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.