New Insights into the Origin and the Genetic Basis of Rhabdomyosarcomas

Rhabdomyosarcomas (RMSs) are the predominant soft-tissue tumors of children and adolescents (Arndt and Crist, 1999). These tumors are generally divided into alveolar rhabdomyosarcoma (aRMS) and embryonal rhabdomyosarcoma (eRMS) subtypes. Most aRMSs are the result of chromosomal translocations betweenPAX3 or PAX7 and FOXO1A genes, resulting in Pax3-FKHR and Pax7-FKHR fusion proteins (Tiffin et al., 2003). These fusion proteins have potent transcriptional activity leading to cellular transformation and oncogenesis into aRMS. On the other hand, a wide range of causative mutations have been implicated in eRMS, such as the loss of heterozygosity at 11p15.5 locus (Anderson et al., 1999), mutations in tumor suppressor p53 (Felix et al., 1992), retinoblastoma (Rb1) (Kohashi et al., 2008), Nand K-ras genes (Stratton et al., 1989), and PTCH1 haploinsuficiency (Hahn et al., 1998). It is thought that eRMSs develop from cells residing within the muscle tissue, partly because eRMSs express markers of muscle cells such as MyoD, Myogenin, and Desmin. Furthermore, these tumors can also occur where muscle tissue resides. However, muscle tissue contains a heterogeneous population of muscle stem cells and downstream myogenic progenitors as well as nonmyogenic cells (Kuang et al., 2007). To study the potentials of individual subpopulations of muscle cells in eRMS development, Rubin et al. (2011) deleted p53 either with or without Ptch1 haploinsuficiency. They then used various Cre drivers to inactivate these genes in muscle stem cells and in proliferating and maturing myoblasts. In a 600 day follow-up period, they observed that all mouse Cre lines developed tumors at the penetrance rate of 13%–56%. Upon histological examination of these tumors, they found a spectrum of malignancies ranging from alveolar and embryonal RMS to undifferentiated pleomorphic sarcomas (UPSs). They observed that rhabdomyosarcomas developed from all subpopulations of muscle cells, including muscle satellite cells and differentiating myoblasts (Figure 1). More importantly, they found that the cell of origin and the mutational profile of the tumors were important in determining the proportion of rhabdomyosarcomas versus undifferentiated spindle cell sarcomas (i.e., UPSs). Loss of p53 in maturing myoblasts (Myf6+ cells) gave rise to the highest percentage of eRMSs. These tumors showed the highest degree of myogenic differentiation potential, while those derived from satellite cells (Pax7+ cells) had the lowest rate of myogenic differentiation in in vitro differentiation assays. To study the effect of retinoblastoma (Rb1) mutation on eRMS development in combination with the loss of p53, Rubin et al. (2011) inactivated both p53 and Rb1 with or without Ptch1 haploinsuficiancy. Loss of Rb1 alone did not lead to tumor initiation. However, unlike Rb1 loss, Ptch1 haploinsuficiency contributed to tumor initiation at every level of cellular differentiation. To further explore the role of Rb1 in rhabdomyosarcomas development, they inactivated both Rb1 and p53 in various subpopulations of muscle progenitor cells using different Cre drivers. Surprisingly, they observed that combination of Rb1 and p53 loss was generally associated with an undifferentiated phenotype in the resulting tumors. Rb1 deletion reduced