p53-mediated hematopoietic stem and progenitor cell competition

Cell competition was originally described in Drosophila as a process for selection of the fittest cells. Using genetic mosaic mouse models and bone marrow chimeras, we have characterized a form of cell competition that selects for the least damaged cells. This competition is controlled by p53 but is distinct from the classical p53-mediated DNA damage response: it persists for months, is specific to the hematopoietic stem and progenitor cells, and depends on the relative rather than absolute level of p53 in competing cells. The competition appears to be mediated by a non-cell autonomous induction of growth arrest and senescence-related gene expression in outcompeted cells with higher p53 activity. p53-mediated cell competition of this type could potentially contribute to the clonal expansion of incipient cancer cells. This microarray experiment is aimed at identification of candidate genes that mediate this competition. It compares mRNA expression patterns of HSCs with different levels of p53 activity in either competitive or non-competitive conditions (isolated from either wild type, mutant p53, or mosaic wt/mutant p53 mice (R26-mp53mice) after irradiation). Wild type (WT), fully recombined R26-mp53, or R26-mp53 mosaic mice were euthanized 3 weeks after exposure to 2.5 Gy. In mosaic mice, cells expressing mutant p53 co-expressed GFP, and WT cells were GFP-negative. HSCs (lineage- c-kit+ Sca-1+ CD48- CD150+ cells) from these mice were FACS sorted from bone marrow into Trizol, and mRNA was amplified followed by hybridization to Illumia chips.