The EWS/FLI translocation product is the causative oncogene in Ewing sarcoma and 
acts as an aberrant transcription factor. EWS/FLI dysregulates gene expression 
during tumorigenesis by abnormally activating or repressing genes. The 
expression levels of thousands of genes are affected in Ewing sarcoma, however, 
it is unknown which of these genes contribute to the transformed phenotype. Here 
we characterize BCL11B as an up-regulated EWS/FLI target that is necessary for 
the maintenance of transformation in patient derived Ewing sarcoma cells lines. 
BCL11B, a zinc finger transcription factor, acts as a transcriptional repressor 
in Ewing's sarcoma and contributes to the EWS/FLI repressed gene signature. 
BCL11B repressive activity is mediated by the NuRD co-repressor complex. We 
further demonstrate that re-expression of SPRY1, a repressed target of BCL11B, 
limits the transformation capacity of Ewing sarcoma cells. These data define a 
new pathway downstream of EWS/FLI required for oncogenic maintenance in Ewing 
sarcoma.