Model–FOXO1 repression in cHL contributes to a block of PC differentiation and is required for high MYC expression. In the absence of FOXO1, JAK/STAT, NF-κB, and IRF4 are not able to induce PRDM1α expression at high levels in cHL. Instead, MYC expression is high. Thus, downregulation of FOXO1 shifts PRDM1α–MYC balance toward MYC, thereby facilitating transformation or maintenance of the cHL oncogenic program. FOXO1 reactivation initiates a negative feed-forward loop resulting in high PRDM1α levels and MYC repression.