Dissecting the relationship between declining lymphoid progenitor fitness and agi

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DESCRIPTION (provided by applicant): This proposal will attempt to characterize how aging-associated increases in inflammation and decreased interleukin-7 receptor (IL-7R) signaling alter hematopoietic B-cell progenitor populations and promote the expansion of Philadelphia Chromosome (Ph+) cells. The incidence of Ph+ B-cell acute lymphoblastic leukemias (B-ALL) increases significantly after age 50. This type of cancer results from the generation of the Philadelphia Chromosome, which creates a constitutively active kinase (Bcr-Abl) in hematopoietic progenitor cell populations. The expression of this oncogene results in unregulated cellular growth. Although the manifestation the Philadelphia Chromosome has been observed in all age groups, Ph+ leukemias are rarely observed in young individuals. Based on this observation the goals of this project are two-fold: 1.To determine the extent of signaling and metabolic changes that occur in aged B-cell progenitors relative to young populations induced by increased inflammation or decreased IL-7R mediated signaling; and 2. To determine if the aging-associated increases in Ph+ B-ALL results from the ability of Bcr-Abl to restore or circumvent identified signaling or metabolic defects found in aged B-cell progenitors. These studies will reveal how aging-associated increases in inflammation and decreases in IL-7R mediated signaling promote leukemogenesis in B-cell progenitor populations. Since age has been described as the single most important prognostic factor in the development of many cancers, this study may help to identify common themes that connect aging-associated cancers of varying etiological origin which could lead to improved therapeutics for various aging-associated malignancies.