Faculty, Staff and Student Publications

Language

English

Publication Date

12-23-2025

Journal

Blood Advances

DOI

10.1182/bloodadvances.2025016801

PMID

40845256

PMCID

PMC12744261

PubMedCentral® Posted Date

8-25-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Mantle cell lymphoma (MCL) is an incurable subtype of B-cell non-Hodgkin lymphoma. Despite multiple approved Bruton tyrosine kinase inhibitors (BTKis), resistance to BTKi continues to pose a major clinical challenge. The transcription factor sex determining region Y-box 11 (SOX11) is expressed in most patients with MCL and is associated with poor outcomes. We have previously demonstrated SOX11-dependent B-cell receptor (BCR) signaling in transgenic models of MCL. Here, we report that SOX11 drives BCR signaling via the transcriptional activation of the PAX5/CD19 axis. The translational potential of these results is significant as single-cell RNA sequencing data show that SOX11 is overexpressed in ibrutinib-resistant patients as compared to ibrutinib-sensitive patients. Treatment with the SOX11 DNA-binding inhibitor (SOX11i) significantly reduces the expression of PAX5, CD19, and components of BCR signaling in both ibrutinib-sensitive and ibrutinib-resistant cell lines. Importantly, SOX11i was able to demonstrate cytotoxicity in cells derived from ibrutinib-resistant, venetoclax (B-cell lymphoma 2 [BCL2] inhibitor), and chimeric antigen receptor T-cell-resistant patient-derived xenograft models in vitro. SOX11i treatment reduced the tumor growth in vivo in an MCL xenograft model without any significant toxicity. SOX11 inhibition offers significant potential for patients with MCL, especially BTKi-resistant patients, by targeting upstream resistance mechanisms.

Keywords

Humans, SOXC Transcription Factors, Lymphoma, Mantle-Cell, Signal Transduction, Receptors, Antigen, B-Cell, Antigens, CD19, Drug Resistance, Neoplasm, PAX5 Transcription Factor, Animals, Cell Line, Tumor, Mice, Agammaglobulinaemia Tyrosine Kinase, Protein Kinase Inhibitors, Adenine, Piperidines, Xenograft Model Antitumor Assays

Published Open-Access

yes

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