The MYC-YBX1 Circuit in Maintaining Stem-like Vincristine-Resistant Cells in Rhabdomyosarcoma

Abstract: Rhabdomyosarcoma (RMS) is a devastating pediatric soft tissue sarcoma with no effective therapy for relapsed disease. There is limited knowledge on the mechanisms underlying treatment failures. We demonstrated that treatment of RMS cells with vincristine led to an increase of CD133-positive stem-like resistant cells. By single cell RNAseq analysis, MYC and YBX1 were among the top-scored transcription factors in CD133-high expressing cells. CRISPR/Cas9-mediated targeting of MYC and YBX1 reduced stem-like characteristics and viability of the vincristine-resistant cells. MYC and YBX1 exhibited mutual regulation with MYC binding to the YBX1 promoter and YBX1 binding the MYC mRNA. A MYC inhibitor, MYC361i, synergized with vincristine to reduce tumor growth and deplete the stem-like cells in a zebrafish model of RMS. MYC and YBX expression showed positive correlation in RMS patients. High expression of MYC correlated with poor survival. Targeting the MYC-YBX1 axis represents a promising option for improving survival of RMS patients.