ABSTRACT
Core regulatory transcription factors (CR TFs) establish enhancers with logical ordering during embryogenesis and development. Here we report that in fusion-positive rhabdomyosarcoma, a cancer of the muscle lineage, the chief oncogene PAX3-FOXO1 is driven by a translocated FOXO1 super enhancer (SE) restricted to a late stage of myogenesis. Using chromatin conformation capture techniques, we demonstrate that the extensive FOXO1 cis-regulatory domain interacts with PAX3. Furthermore, RNA sequencing and chromatin immunoprecipitation sequencing data in tumors bearing rare PAX translocations implicate enhancer miswiring across all fusion-positive tumors. HiChIP of H3K27ac showed connectivity between the FOXO1 SE, additional intra-domain enhancers, and the PAX3 promoter. We show that PAX3-FOXO1 transcription is diminished when this network of enhancers is ablated by CRISPR. Our data reveal a hijacked enhancer network that disrupts the stepwise CR TF logic of normal skeletal muscle development (PAX3 to MYOD to MYOG), replacing it with an "infinite loop" enhancer logic that locks rhabdomyosarcoma in an undifferentiated stage.
ABSTRACT
OBJECTIVES: To assess the outcome of a myringoplasty procedure during a 5-year period at a tertiary teaching hospital in Abha, Kingdom of Saudi Arabia. METHODS: All patients with chronic suppurative otitis media (CSOM) who underwent elective myringoplasty between August 2012 and February 2018 were included in the study. Patients were investigated preoperatively and postoperatively by pure tone audiometry (PTA). The patients' demographic data were collected together with the surgical outcome. Postoperatively, patients were followed at the first week, at 6 weeks and then every 3 months, thereafter for one year. RESULTS: A total of 67 myringoplasty procedures were performed during the period of study. There were 41 females and 26 males, and they had an age range of 16-60 years and a mean age of 32.37±12.95 years. Preoperative PTA indicated that 58 (86.6%) patients had a hearing gap greater than 20 dB. However, after surgery, only 9 (13.4%) patients remained with hearing gaps greater than 20 dB. The success rate of graft stability at the end of one year was 94% with significant difference p=0.0001. However, one patient of the 4 patients with failed graft stability demonstrated graft atrophy, and the remaining 3 developed graft infection. Conclusion: Myringoplasty remains a useful technique for the management of CSOM. However, it depends on the surgeon's skills and expertise and on the site of perforation. The success rate of myringoplasty in this study was comparable with that of the quoted literature.