The amplified MYC oncogene in DLBCL and BL lymphoma strongly stimulates RiBi that supports cell proliferation and tumor progression through enhanced protein synthesis. Blocking RiBi with ActD or the pol-I inhibitor CX5461 decreases ribosome numbers impacting abnormal proliferation. In parallel, the IRBC comprising 5S rRNA, RPL5, and RPL11 is formed that blocks mdm2 to activate p53. p53 interferes with proliferation through induction of p21 and stimulates ubiquitination of the antiapoptotic BCL-2 family member MCL-1 that is frequently amplified in MYC-driven lymphomas. Ubiquitinated MCL-1 is then degraded in the proteasome to free BAK-BAX dimers that trigger mitochondrial membrane disruption and apoptosis, leading to tumor regression.