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

描述（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，以最大限度地提高生殖成功率。我们假设，适应性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/表观遗传变化通常在适应性良好的细胞群体中是不利的。尽管如此，随着年龄的增长，累积的损伤和增加的炎症可能会改变自我更新细胞群的细胞适应性，

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.