Our long-term goal in this project is to elucidate the molecular and cellular biology for Ewing Sarcoma development and translate this knowledge into advances for pediatric cancer. Ewing sarcoma, the second most common pediatric malignant bone tumor, is characterized by a chromosomal translocation t(11;22). The resulting fusion oncoprotein EWS/FLI is an aberrant transcription factor necessary for oncogenic transformation in Ewing cells. EWS acts as an amino-terminal transcriptional activation domain linked to the carboxy-terminal DNA-binding domain of its ETS family member partner in crime, FLI. Microsatellite repeats characterized by the motif GGAA serve as binding sites for EWS/FLI within the promoters of upregulated target genes in Ewing Sarcoma. Previously thought of as ?junk DNA,? these polymorphic microsatellites serve as response elements for EWS/FLI DNA binding with interesting genetic correlations and possible clinical implications. Though EWS/FLI both activates and represses numerous target genes directly and indirectly, how EWS/FLI distinguishes whether to up or down regulate gene expression remains undetermined. Therefore, the experiments proposed herein aim to test the hypothesis that EWS/FLI induces oncogenic transformation and regulation of transcriptional activation via GGAA microsatellites whose length dictates both binding and effector function. Thus our aims are: 1) Determine to what extent GGAA microsatellites function as enhancer response elements and 2) Determine the role of GGAA motif length in transcriptional activation in Ewing Sarcoma. This project is an important approach to pediatric cancer because it provides a model of understanding oncogenic transcriptional regulation necessary for biomarker and therapeutic development to improve patient care and overall survival.
Ewing Sarcoma is a pediatric bone malignancy driven by a genetic mutation that generates the fusion oncogenic driver EWS/FLI. As the exact mechanisms governing this molecular aberrancy are unknown, this proposal endeavors to better elucidate the process. Successful completion of these studies will provide molecular understanding critical to discover and/or develop more effective therapies to treat patients with this disease and provide a model for understanding the molecular complexities of other pediatric cancers.
| Johnson, Kirsten M; Mahler, Nathan R; Saund, Ranajeet S et al. (2017) Role for the EWS domain of EWS/FLI in binding GGAA-microsatellites required for Ewing sarcoma anchorage independent growth. Proc Natl Acad Sci U S A 114:9870-9875 |
| Johnson, Kirsten M; Taslim, Cenny; Saund, Ranajeet S et al. (2017) Identification of two types of GGAA-microsatellites and their roles in EWS/FLI binding and gene regulation in Ewing sarcoma. PLoS One 12:e0186275 |
