SOX11 Cooperates with CCND1 in Mantle Cell Lymphoma Pathogenesis

MCL (Mantle cell lymphoma) is an aggressive and incurable B cell malignancy with a median survival of 5-6 years. Cyclin D1 (CCND1) overexpression is a key diagnostic feature of this disease, observed in more than 90% of MCL tumors.  However, murine models over-expressing CCND1 in B cells do not recapitulate the phenotype of MCL.  The SOX11 transcription factor is aberrantly expressed in 80-90% of primary MCL.  Our published data demonstrated that SOX11 binds and functionally regulates key components in multiple oncogenic pathways in MCL such as WNT and TGFβ pathways.  Recent studies have also showed that SOX11 regulates PAX5 and PDGFA to block differentiation and facilitate lymphoma growth.  We thus hypothesize that SOX11 expression may contribute directly and functionally cooperate with CCND1 in MCL pathogenesis.

To study the role of SOX11 in MCL tumorigenesis in vivo, we have generated a novel SOX11 transgenic mouse model with B cell-specific tissue expression under the E-mu enhancer and an IRES-eGFP tag to monitor the expression of SOX11.  The presence of SOX11 can be readily detected in pre-pro-B stage in the bone marrow coincided with the activation of E-mu enhancer and was persistent through all stages of B cells. SOX11 over-expression in our mouse model led to an aberrant oligo-clonal expansion of CD19+/CD5+ B cells.  This phenotype was evident in all SOX11 transgenic mice studied (100% penetrance, n= 42 mice) with an average of 7-12 fold increase (p<0.03) of the CD5+ B cell populations as compared to littermate controls starting from 1.5 months.  Using Mass Cytometry (CyTOF), we further characterized this B cell population to be CD23-, CD21/35 dim, CD138-, high surface IgM, and variable IgD expression, a naive B cell phenotype consistent with an early precursor stage of human MCL.  This MCL phenotype is most prominent in peripheral blood and spleen and, to a much lesser extent, in peritoneal cavity and bone marrow.  Transplanting bone marrow from SOX11 transgenic mouse to lethally-irradiated wild type mice successfully transferred the observed phenotypic CD19+/CD5+/CD23- B cell hyperplasia, suggesting that SOX11 overexpression in early B cells drives this MCL phenotype.

We next studied the cooperation between CCND1 and SOX11 by crossing SOX11 transgenic mice with a CCND1 transgenic mouse model, which over-expresses CCND1 in a B-cell specific manner under a similar E-mu enhancer.  Overexpression of both CCND1 and SOX11 in the double transgenic mice model dramatically enhanced (average 10x, range 6x-30x) the aberrant MCL phenotype (CD19+/CD5+/CD23-) in peripheral blood, spleen, bone marrow, peritoneal cavity and lymph nodes compared to age-matched SOX11 and CCND1 single-transgenic mice.

We report here the first direct evidence in vivo that SOX11 expression drives an aberrant expansion of B cells consistent with early human MCL and functionally collaborates with CCND1 in “full blown” MCL pathogenesis, mimicking the commonly observed co-expression of SOX11 and CCND1 in most human MCL tumors. This model captures the underpinning molecular pathogenesis events occurred in the majority of human MCL and overcomes constraints of previous MCL models that develop a phenotype after long latency or with low penetrance, making it a valuable tool for testing anti-MCL therapeutics. We are currently developing small molecule SOX11 inhibitors using SOX11 DNA binding domain models and consensus SOX11 binding nucleotides to screen a large library of compounds to identify new therapeutics for this fatal disease and gain better understanding of the molecular mechanisms of MCL tumorigenesis.