Advanced science (Weinheim, Baden-Wurttemberg, Germany)Jul 17, 2026

SOX5 May Drive Cancer Progression by Changing Gene Control in MYC-Driven B-Cell Lymphoma

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Updated Jul 18, 2026

Abstract

SOX5 is identified as an early-stage epigenetic modifier in MYC-driven B-cell lymphoma.

Single-cell transcriptomics reveal a highly proliferative B-cell compartment with increased SOX5 transcripts at an early stage.
SOX5 influences a specific chromatin program characterized by new binding at promoters and reduced promoter accessibility.
Binding of SOX5 at the PCNP promoter leads to decreased transcription, which may lower apoptosis and relieve cell cycle arrest.
Targeting SOX5 using B-cell-specific viral vectors reduces the population of malignant B cells and partially restores normal tissue structure.
SOX5's role in maintaining an early-stage proliferative state in B-cell lymphoma suggests it could be a target for therapeutic strategies.

Simplified

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)-shSOX5 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.

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SOX5 May Drive Cancer Progression by Changing Gene Control in MYC-Driven B-Cell Lymphoma

Abstract

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