Aging-associated alterations in adaptive landscapes and the evolution of leukemia

描述（由申请人提供）：长寿动物的进化需要获得有效的肿瘤抑制机制，以最大限度地提高繁殖成功率。我们假设，良好适应的干细胞的进化赋予了对致癌突变的抗性，因为改变表型的遗传/表观遗传变化在良好适应的细胞群体中通常是不利的。尽管如此，随着年龄的增长，损伤的积累和炎症的增加可能会改变自我更新细胞群的细胞适应性， 通过对干细胞及其生态位造成损害，或通过改变细胞发育程序（如造血）。微环境的改变以及特定干细胞和祖细胞群体适应性的降低将改变适应性景观，选择在此背景下具有适应性的特定致癌突变。专注于造血系统和使用小鼠模型，拟议的研究将分析老年B祖细胞健康下降的机制，以及适应性景观中与年龄相关的改变如何促进对特定致癌突变的选择。我们将1）确定观察到的B祖细胞中的年龄相关变化是否是由于造血干细胞谱系偏好的改变，2）询问小鼠中炎症和细胞因子受体信号传导的操纵是否可以影响造血祖细胞适应性、致癌适应和白血病发生中的年龄相关减少，和3）剖析在老年人中B淋巴细胞生成受损和特定癌基因选择增加的分子机制。这些研究应该揭示衰老，炎症，造血和白血病发生之间的重要联系，并可能提出减少老年癌症发展的策略。

DESCRIPTION (provided by applicant): The evolution of long-lived animals has necessitated acquisition of potent tumor suppressive mechanisms to maximize reproductive success. We hypothesize that the evolution of well-adapted stem cells has conferred resistance to oncogenic mutations, as phenotype- altering genetic/epigenetic change should typically be disadvantageous within a well-adapted cell population. Nonetheless, accumulating damage and increased inflammation with age could alter the cellular fitness of self-renewing cell populations, both by causing damage to stem cells and their niche, or by altering cell developmental programs (such as for hematopoiesis). Alterations in microenvironments together with reductions in the fitness of particular stem and progenitor cell populations will then change the adaptive landscape, selecting for specific oncogenic mutations that are adaptive within this context. Focusing on the hematopoietic system and using mouse models, proposed studies will analyze the mechanisms underlying declining B-progenitor fitness in old age, and how age-associated alterations in the adaptive landscape promote selection for particular oncogenic mutations. We will 1) determine whether observed age-associated changes in B-progenitors are due to alterations in hematopoietic stem cell lineage bias, 2) ask whether manipulation of inflammation and cytokine receptor signaling in mice can impact on aging-associated reductions in hematopoietic progenitor fitness, oncogenic adaptation and leukemogenesis, and 3) dissect the molecular mechanisms underlying impaired B-lymphopoiesis and increased selection for particular oncogenes in old age. These studies should reveal important links between aging, inflammation, hematopoiesis, and leukemogenesis, and could suggest strategies to reduce cancer development with advanced age.