After we have learned a great deal about the roles of p53 in ES cells in the past four years, my team initiated a project to study the roles of p53 in mesenchymal stem cells (MSCs) in FY2013. Because MSCs are a type of adult stem cells, we believe that this new project complements our existing studies in ES cells. This initiative aligns well with the mission of the National Cancer Institute (NCI). To effectively address the challenges in the field of MSCs, I have drawn a roadmap for this new project. Using flow cytometry, we have successfully isolated a population of multi-potent cells from mouse bone marrow. These primary cells are able to carry out tri-lineage differentiation, becoming osteoblasts, adipocytes, and chondrocytes under inductive conditions. Therefore, these cells are functionally defined as mesenchymal stem cells (MSCs). Our preliminary results showed that p53 plays a role in controlling the osteogenesis of these MSCs. In addition, we delineated the molecular mechanism underlying the lineage control of these cells by p53. We found that p53 induces miR34s, which suppresses the translation of Runx2 in MSCs. Thus, p53 indirectly represses Runx2, a key transcription regulator of osteogenic differentiation. We have published these observations in Stem Cells (33: 1304-1319, 2015). Because MSCs are one of the cell-of-origins of OS, we plan to study the roles of Runx2 in osteosarcoma cells. We found that RUNX2 induces MYC expression only in OS cells but not in normal MSCs. Mechanistically, RUNX2 recruits an epigenetic complex, the Menin/MLL1 complex, to induce MYC expression. In the next several years, we plan to study the regulatory mechanisms of other survival factors in OS cells.
