SOX5 Orchestrates Malignant Evolution via Promoter‐Centric Chromatin Remodeling in MYC‐Driven B‐Cell Lymphoma

ABSTRACT Early events that bias germinal‐center B cells toward malignant evolution remain incompletely defined. Here, we uncover Sex‐determining Region Y Box 5 ( SOX5 ) as an early‐stage epigenetic modifier in myelocytomatosis oncogene ( MYC )‐driven B‐cell lymphoma. Single‐cell transcriptomics of lymph nodes from CRISPR/Cas9‐engineered Myc ^Cd19‐Cre B‐cell lymphoma chimeric mice resolve a Ki67–high proliferative compartment at an early stage with enriched SOX5 transcripts. CRISPRa, CRISPR knockout, and multi‐omic profiling reveal a SOX5 ‐centered chromatin program defined by de novo promoter‐proximal occupancy coupled to contraction of promoter accessibility. Mechanistically, SOX5 binding at the Proteolytic Signal‐Containing Nuclear Protein ( PCNP ) promoter represses its transcription, thereby reducing apoptosis and alleviating G2/M arrest. Consequently, B‐cell–targeted adeno‐associated virus 6 (AAV6)‐sh SOX5 reduces Ki67‐positive PAX5 ‐positive malignant B cells and partially restores follicular architecture. Together, SOX5 ‐mediated, promoter‐centric repression of PCNP and other effectors installs and maintains an early‐stage proliferative state in MYC ‐driven B‐cell lymphoma, which nominates SOX5 ‐directed intervention as a candidate therapeutic strategy for further investigation.