TC32 Ewing''s Sarcoma Transcriptome

Ewing sarcoma is a bone and soft-tissue sarcoma that depends on the continued activity of the EWS-FLI1 transcription factor, which is formed by the t(11;22)(q24;q12) chromosomal translocation. This translocation leads to the fusion of the binding domain of the ETS family member FLI1 to the transactivation domain of EWSR1 and the loss of negative regulatory domains. The result is a constitutively active transcription factor that both drives and suppresses the expression of more than 500 genes. We also show that the second-generation trabectedin analog lurbinectedin (PM01183) caused the same nuclear redistribution of EWS-FLI1, leading to a loss of binding of EWS-FLI1 at target sequences and elimination of EWS-FLI1 activity at the promoter, mRNA, and protein levels of expression. In order to show that these effects are not restricted to these selected targets, we evaluated the effect of treatment on the gene signature of EWS-FLI1 using RNA sequencing.