SOX11 expression is restricted to EBV-negative Burkitt lymphoma and is associated with molecular genetic features

• SOX11 expression and EBV infection occur in alternative subsets of BL with different profiles of somatic mutations.

• Among EBV⁻ BL, IG∷MYC translocation is generated by class switch recombination in SOX11⁺ BL and somatic hypermutation in SOX11⁻ tumors.

SRY-related HMG-box gene 11 (SOX11) is a transcription factor overexpressed in mantle cell lymphoma (MCL), a subset of Burkitt lymphomas (BL) and precursor lymphoid cell neoplasms but is absent in normal B cells and other B-cell lymphomas. SOX11 has an oncogenic role in MCL but its contribution to BL pathogenesis remains uncertain. Here, we observed that the presence of Epstein-Barr virus (EBV) and SOX11 expression were mutually exclusive in BL. SOX11 expression in EBV-negative (EVB^-) BL was associated with an IG∷MYC translocation generated by aberrant class switch recombination, whereas in EBV-negative (EBV⁻)/SOX11-negative (SOX11⁻) tumors the IG∷MYC translocation was mediated by mistaken somatic hypermutations. Interestingly, EBV⁻ SOX11-expressing BL showed higher frequency of SMARCA4 and ID3 mutations than EBV⁻/SOX11⁻ cases. By RNA sequencing, we identified a SOX11–associated gene expression profile, with functional annotations showing partial overlap with the SOX11 transcriptional program of MCL. Contrary to MCL, no differences on cell migration or B-cell receptor signaling were found between SOX11⁻ and SOX11-positive (SOX11⁺) BL cells. However, SOX11⁺ BL showed higher adhesion to vascular cell adhesion molecule 1 (VCAM-1) than SOX11⁻ BL cell lines. Here, we demonstrate that EBV⁻ BL comprises 2 subsets of cases based on SOX11 expression. The mutual exclusion of SOX11 and EBV, and the association of SOX11 with a specific genetic landscape suggest a role of SOX11 in the early pathogenesis of BL.