Distinct Transcriptional Regulatory Domain Identified in Ewing Sarcoma Fusion ProteinDistinct Transcriptional Regulatory Domain Identified in Ewing Sarcoma Fusion Protein https://pediatricsnationwide.org/wp-content/uploads/2021/09/AdobeStock_221145581-1024x1024.jpg 1024 1024 Lauren Dembeck Lauren Dembeck https://pediatricsnationwide.org/wp-content/uploads/2021/03/Dembeck_headshot.gif
- October 06, 2021
- Lauren Dembeck
A better understanding of a newly defined region in the fusion protein that causes Ewing sarcoma may lead to novel approaches for therapeutic targeting.
Ewing sarcoma is an aggressive pediatric bone cancer defined by the presence of a single genetic abnormality: a chromosomal translocation. The translocation splits two genes and joins them abnormally, creating a fusion called EWS/FLI. The EWS/FLI protein broadly alters gene expression of the affected cell thereby initiating tumor growth.
Researchers at Nationwide Children’s Hospital have discovered that a small part of the FLI half of the protein is required for EWS/FLI to fully alter gene expression and cause cancer. The findings were published in the journal Oncogene.
“We have known for a long time that EWS/FLI is the key to Ewing sarcoma,” explains senior author Stephen Lessnick, MD, PhD, director of the Center for Childhood Cancer & Blood Diseases in the Abigail Wexner Research Institute at Nationwide Children’s. “We have always believed that if we can understand how EWS/FLI works, then we can use that knowledge to block its function, stop cancerous growth and cure Ewing sarcoma.”
The EWS portion of the protein is an intrinsically disordered transcriptional regulatory domain. “It does not form a consistent 3-dimensional structure. This shape-shifting ability makes it an unsuitable drug target,” explains Dr. Lessnick. The FLI portion contains a DNA-binding domain flanked by two regions of unknown function.
“Because DNA binding domains of this type have conserved structures, no one studied the FLI portion carefully, and data on the flanking regions were conflicting,” adds Dr. Lessnick, who is also a professor of pediatrics at The Ohio State University College of Medicine.
To dissect the functions of FLI portion, first author Megann Boone, PhD, who recently graduated from Dr. Lessnick’s laboratory, removed endogenous EWS/ FLI from a Ewing sarcoma cell line — rendering it non-cancerous — and then re-introduced a series of genetically-engineered EWS/FLI mutants with alterations in the FLI portion.
“A number of years ago, my team developed this method,” explains Dr. Lessnick. “With it, we can ask a simple question: Which portions of EWS/FLI are required to make the cells cancerous again?”
The experiments revealed a previously unknown region, adjacent to the DNA binding domain, that is absolutely required for full transcriptional function, and thus, cancer development. This finding was completely unexpected.
“We always assumed that the only role of the FLI portion was to bind DNA. Only by shedding this assumption was Megann able to identify this new function that is critical for EWS/FLI-mediated sarcomagenesis,” says Dr. Lessnick. “This study exemplifies why it is so important for people ‘with fresh eyes’ to come into labs and look at problems differently. Indeed, this is why we have a research institute next to the hospital: It drives innovative translational work that bridges science and pediatric medicine, and will ultimately revolutionize therapeutic approaches to devastating pediatric diseases.”
This article appears in the 2021 Fall/Winter print issue. Download the full issue.
Boone MA, Taslim C, Crow JC, Selich-Anderson J, Byrum AK, Showpnil IA, Sunkel BD, Wang M, Stanton BZ, Theisen ER, Lessnick SL. The FLI portion of EWS/FLI contributes a transcriptional regulatory function that is distinct and separable from its DNA-binding function in Ewing sarcoma. Oncogene. 2021 Jul;40(29):4759-4769.
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