Permissive Chromatin Environment In Cell Of Origin Allows For Aberrant Targeting of Chimeric Oncoprotein EWS-FLI

Chromosomal translocations involving transcription factor genes have been identified in an increasingly wide range of cancers. Some translocations can create a protein ‘‘chimera’’ that is composed of parts from different proteins. How such chimeras cause cancer, and why they cause cancer in some cell types but not others, is not understood. EWS–FLI is a translocation-associated chimera found in virtually all cases of Ewing Sarcoma, a highly malignant bone and soft tissue tumor of children and young adults. We have shown that in tumor cells EWS-FLI binds a specific DNA sequence distinct from its parental transcriptional factor FLI1. However in other cell types EWS-FLI binds the FLI1 canonical motif.  This led us to hypothesize that the chromatin environment within the cell of origin for Ewing Sarcoma is permissive for the binding of the aberrant transcription factor EWS-FLI.  Therefore, we investigated the chromatin landscape of primary human mesenchymal stem cells (MSCs). We found that chromatin organization in MSC bears striking resemblance to that of Ewing Sarcoma but different from virtually all other cells types tested suggesting that MSC is the cell of origin for this cancer. In particular, regions targeted by the oncogene EWS-FLI in tumor cells is nucleosome depleted in MSC.   Regions showing the most difference in nucleosome depletion between the cancer and stem cell are correlated with intensity of EWS-FLI binding.  Together these data suggest that MSCs are epigenetically primed for targeting by EWS-FLI through a unique chromatin environment.