Cells heterozygous for p53 mutation undergo loss of the WT p53 allele by a process termed loss of heterozygosity (p53LOH) which leads to cancer development. The aim of this study was to challenge the hypothesis that p53LOH occurring in adult stem cells is an initiating event leading to cancer. Interestingly, p53LOH already occurred in the bone marrow (BM) of heterozygous p53 mutant mice, where it may either involve the loss of WT or mutant p53 allele, with a preference of losing the mutant allele. However, in-vitro established mesenchymal stem cells (MSCs) isolated from BM of heterozygous p53 adult mice, underwent exclusively WT p53LOH and were able to generate tumors in-vivo. WT p53LOH was facilitated with age. Analysis of the gene expression profile along the LOH process in heterozygous p53 MSCs has indicated Homologous Recombination (HR) DNA repair pathway, which is known to be p53 transcription-independent, was up-regulated. Likewise, the expression of Smarca1, a chromatin remodeler, was induced. Importantly, Smarca1 up-regulation was observed during p53LOH process also in Mouse Embryonic Fibroblasts (MEFs). Our results suggest that p53LOH process, occurring in adult stem cells such as MSCs, would raise their risk to become tumor initiating cells.
