A gene mutation could be a driving factor in the development of Ewing’s sarcoma

Katherine Trujillo Useche

Latin Agency for Medicine and Public Health News

The gene known as RING1B is the key to the development of Ewing’s sarcoma, a malignant bone tumor, which forms in bone or soft tissue and mainly affects adolescents and young adults. The discovery opens the door to the development of new therapeutic strategies.

At the Sant Joan de Déu Research Institute (IRSJD), researchers in collaboration with the Center for Genomic Regulation (CRG), found that the RING1B gene is critical for the development of Ewing’s sarcoma, which is a rare type of cancer. . occurs in bones and soft tissues. This new epigenetic vulnerability in cancer cells opens the door to the development of therapeutic strategies.

Ewing’s sarcoma is caused by a chromosomal translocation, where the EWSR1 gene on chromosome 22 fuses with the -FLI1 gene, is the main driver of tumorigenesis thanks to the transcriptional activation mechanism of EWSR1 and the DNA binding domain of FLI1.

The study published in Science Advances describes how the EWSR1-FLI1 oncogenic function protein is addressed to different parts of the genome by RING1B, allowing this protein to hijack the transcriptional program of cells, transforming them into cancer cells.

Scientists found that RING1B and EWSR1-FLI1 are located in the same regions of the genome, where RING1B is responsible for the recruitment of EWSR1-FLI1. Therefore, EWSR1-FLI1 cannot activate its target genes and transform a healthy cell into a cancerous one without RING1B. Experts showed that the tumors worsened when RING1B expression was reduced

“Our results offer surprising information on the mechanism of Ewing’s sarcoma, finally approaching the discovery of the cell of origin of this rare type of cancer,” explains Luciano Di Croce, ICREA research professor at CRG and one of the authors of the study. “All we have to do is look for high levels of RING1B.”

A stimulating therapeutic goal

Epigenetic inhibitors have previously been proposed to treat Ewing’s sarcoma and other types of pediatric cancers such as neuroblastoma, rhabdomyosarcoma, or synovial sarcoma. Future research could explore the pharmacological inhibition of RING1B as a clinical therapy for its treatment.

“EWSR1-FLI1 continues to be a challenging therapeutic target, so understanding its addictions may offer alternative strategies to disconnect its aberrant transcription program,” says Sara Sara Sánchez Molina, first author of the study and postdoctoral researcher at the Institute. of research Sant Joan de Déu. .

“Ewing’s tumors are paradigmatic examples of developmental tumors, where the first genetic or epigenetic stroke occurs during pregnancy and in most of them develops postnatally during specific stages of the Barcelona Center for Pediatric Oncology, Research Institute Sant Joan de Déu and director of the studio.

The study supports the model by which embryonic stem cells characterized by high levels of RING1B are able to maintain the aberrant transcriptional program caused by the oncogenic fusion protein. Ewing’s sarcoma will develop if the individual is born with fusion oncoprotein precursor cells.