The longevity of organisms is maintained by stem cells. If an organism loses the ability to maintain a balance between quiescence and differentiation in the stem/ progenitor cell compartment due to aging and/or stress, this may result in death or age-associated diseases, including cancer. Ewing sarcoma is the most lethal bone tumor in young patients and arises from primitive stem cells. Here, we demon-
IntroductionEwing sarcoma is an aggressive disease that predominantly afflicts children and young adults, in which cancer cells proliferate in bones and soft tissues. 1 The Ewing sarcoma gene (EWS) encodes an RNA binding protein whose specific functional targets are largely unknown, 2 but abnormal fusion between the EWS N-terminus and the C-terminus of various transcription factors is thought to be the primary cause of Ewing sarcoma. 3 The t(11;22)(q24;q12) translocation, which fuses the EWS and Fli-1 (Friend leukemia virus integration 1) genes, accounts for most cases of Ewing sarcoma. The chromosomal translocation creates a chimeric oncogene encoding a transactivating domain from the EWS protein and the DNA binding domain of Fli-1. 3 EWS-Fli-1 expression results in a bypass of cellular senescence, 4 implying a molecular link between EWS and cellular senescence.Unexpectedly, ectopic expression of EWS-Fli-1 in primary cells or cell lines induces growth arrest or cell death rather than promoting cellular transformation, suggesting that cellular context is critical for the oncogenic potential of EWS-Fli-1. 5 Recent studies have demonstrated that human and mouse bone marrow (BM) mesenchymal stem cells expressing EWS-Fli-1, when engrafted into NOD/SCID mice, induce a malignancy with similar pathologic features as Ewing sarcoma. 6,7 These data indicate that mesenchymal stem cells provide a permissive environment for EWS-Fli-1-mediated transformation, suggesting that Ewing sarcoma occurs at the level of stem/progenitor cells. Consistent with this observation, ectopic expression of an EWS-ERG fusion protein in hematopoietic progenitor cell results in leukemia. 8 In addition, Cre-mediated activation of EWS-Fli-1 in Cre-inducible EWS-Fli-1 mice results in rapid development of myeloid/erythroid leukemia, thereby strengthening the molecular link between this oncogene and hematopoietic malignancy. 3