**Abstract**

Sarcomas are heterogeneous cancers of bone or soft tissue. They occur in children, adolescents, and young adults (AYAs). Herein, the subgroup of fusion-positive (FP) sarcomas is characterized by chromosomal rearrangements generating pathognomonic fusion transcripts and oncoproteins. In Ewing sarcoma (EwS), FP-rhabdomyosarcomas (FP-RMS) and synovial sarcomas (SyS), the most common and aggressive forms of sarcomas in childhood and adolescence, the oncogenic rearrangements involve transcription cofactors such as by FET-ETS, PAX3/7-FOXO1 or SS18-SSX fusion oncogenes in EwS, FP-RMS, or SyS, respectively causing widespread epigenetic rewiring and aberrant gene expression. Regardless of these translocations, few recurrent mutations are observed in these sarcomas that may contribute to disease; thus, it is of particular interest to consider the consequences of these translocations for tumor development. Results of current research examining the disease, analyzing, and classifying the role of associated rearrangements of chromatin, and investigating possibilities for tumor-specific intervention such as blocking the transcriptional activity of the fusion protein, or the processes caused by this activity are summarized here and some resulting therapeutic opportunities are presented.

**Keywords:** fusion-positive sarcoma, epigenetic rewiring, aberrant gene expression, targeted therapy
