Medulloblastoma is the most common malignant brain tumor of childhood. The highest-risk tumors are driven by recurrent Myc amplifications (Myc-MB) and experience poorer outcomes despite intensive multimodal therapy. The Myc transcription factor defines core regulatory circuitry for these tumors and acts to broadly amplify downstream pro-survival transcriptional programs. Therapeutic targeting of Myc directly has proven elusive, but inhibiting transcriptional cofactors may present an indirect means of drugging the oncogenic transcriptional circuitry sustaining Myc-MB. Independent CRISPR-Cas9 screens were pooled to identify conserved dependencies in Myc-MB. We performed chromatin conformation capture (Hi-C) from primary patient Myc-MB samples to map enhancer-promoter interactions. We then treated in vitro and xenograft models with the dual CDK9/7 inhibitor zotiraciclib to evaluate effect on Myc-driven programs and tumor growth. Eight CRISPR-Cas9 screens performed across three independent labs identify CDK9 as a conserved dependency in Myc-MB. Myc-MB cells are susceptible to CDK9 inhibition, which is synergistic with concurrent inhibition of CDK7. The dual CDK9/7 inhibitor zotiraciclib disrupts enhancer-promoter activity in Myc-MB and downregulates Myc-driven transcriptional programs, exerting potent anti-tumor effect. Overall design: Myc-amplified D458 or D425 cell lines were established in culture and then treated with either atuveciclib, TG02, or equivalent DMSO control. We then performed gene expression profiling from RNA-seq at the indicated timepoints. UPDATE: [Jan-11-2025] The titles and treatment information were updated for Samples GSM8267116-GSM8267127.