Abstract
Rhabdomyosarcoma (RMS) and Ewing sarcoma (ES) are among the most common pediatric sarcomas (Arndt et al., 2012). Despite sarcomas representing a highly heterogeneous group of tumors, ES and alveolar RMS (ARMS) typically share one common genetic characteristic, namely a specific chromosomal translocation (Helman and Meltzer, 2003; Lessnick and Ladanyi, 2012). These translocations generate fusion proteins, which are composed of two transcription factors (TF). Typically, one TF is a developmentally regulated factor that is essential for proper specification of a given lineage and provides the DNA-binding domain, while the partner TF contributes a transactivation domain that drives aberrant expression of target genes. Based on these common genetic characteristics, the first ESF-EMBO research conference entitled “Molecular Biology and Innovative Therapies in Sarcomas of Childhood and Adolescence” with special focus on RMS and ES was held at the Polonia Castle in Pultusk, Poland. The conference gathered 70 participants from more than 15 countries and several continents representing most research groups that are active in this field.
Highlights
Alveolar RMS (ARMS) harbors reciprocal chromosomal translocations between chromosome 2 and chromosome 13, yielding t (2;13), or t (1;13). These translocations lead to expression of characteristic fusion proteins that consist of the DNA-binding domain of PAX3 or PAX7 and the transactivation domain of the forkhead transcription factor FOXO1 on chromosome 13
Ewing sarcoma (ES) on the other hand is characterized by a translocation involving the ubiquitously expressed, putative RNA-binding EWSR1 gene and the friend leukemia integration 1 (FLI1) transcription factor, forming the EWS/FLI1 fusion protein as the most common fusion event
Available mouse models for alveolar RMS (ARMS) using PAX3/FOXO1 as oncogenic driver as well as attempts to generate a mouse model for ES based on expression of EWS/FLI1 have unraveled the importance of largely unknown secondary hits which are required for tumorigenesis
Summary
Alveolar RMS (ARMS) harbors reciprocal chromosomal translocations between chromosome 2 (or chromosome 1) and chromosome 13, yielding t (2;13), or t (1;13). One such indirect possibility might lie in the epigenetic control of gene expression which seems to play a major role in sarcomas, as discussed during the conference. TUMOR BIOLOGY OF SARCOMA Different levels of gene regulation by EWS/FLI1 were discussed by H.
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