The researchers compared radiation sensitivity in OLIG2-high and OLIG2-low tumors in patient-derived xenograft (PDX) lines and assessed OLIG2 expression in a panel of mouse MYC-amplified medulloblastoma (MB) tumors, patient MB samples, and PDX tumors. The researchers compared OLIG2 inhibition by OLIG2-CRISPR with the small molecule inhibitor CT-179 in combination with radiation for tumor progression in PDX models. Based on OLIG2 protein expression, they showed that MYC-associated MB might be classified into OLIG2-high and OLIG2-low tumors. Tumors with OLIG2-low expression were very susceptible to radiation and infrequently relapsed in MYC-amplified MB PDX models, whereas tumors with OLIG2-high expression was resistant to radiation and frequently progressed to relapse. Irradiation was effective at killing most of the tumor cells in OLIG2-high tumors, however examination of the cerebellar tumor bed performed immediately after radiation therapy revealed the presence of a limited number of tumor cells consisting of OLIG2 and rare OLIG2+ tumor cells. Every single patient that had any resistant tumor cells in their bodies relapsed. The cellular makeup of the recurrent cancers, including the increased expression of OLIG2, was similar to that of the initial tumors. Using CRISPR-mediated deletion or the small chemical inhibitor CT-179, researchers showed that OLIG2 disruption inhibited recurrence from the remaining radioresistant tumor cells, proving that OLIG2 was crucial for recurrence. According to the researchers’ findings, OLIG2 is both a biomarker and an efficient therapeutic target in a high-risk subset of MYC-amplified MB, and the combination of an OLIG2 inhibitor with radiotherapy constitutes a novel and effective method of treating this fatal disease.