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。我们假设，适应良好的干细胞的进化已经赋予了对致癌突变的抵抗力，因为表型改变的遗传/表观遗传变化在适应良好的细胞群体中通常是不利的。尽管如此，随着年龄的增长，损伤的累积和炎症的增加可能会改变自我更新细胞群体的细胞适应性， 无论是通过对干细胞及其利基造成损害，还是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合度的降低将改变适应环境，选择在这种背景下适应的特定致癌突变。以造血系统为重点，利用小鼠模型，拟议的研究将分析老年B祖细胞适合性下降的机制，以及适应环境中与年龄相关的变化如何促进对特定癌基因突变的选择。我们将1)确定观察到的与年龄相关的B祖细胞变化是否是由于造血干细胞谱系偏向的改变，2)询问小鼠炎症和细胞因子受体信号的操纵是否可以影响与衰老相关的造血祖细胞适合性、致癌适应和白血病发生的降低，以及3)剖析导致B淋巴细胞生成受损和老年时对特定癌基因的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，并可能提出减少高龄癌症发展的策略。

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.