SOX11 augments BCR signaling to drive MCL-like tumor development

Abstract

Mantle cell lymphoma (MCL) is characterized by increased B-cell receptor (BCR) signaling, and BTK inhibition is an effective therapeutic intervention in MCL patients. The mechanisms leading to increased BCR signaling in MCL are poorly understood, as mutations in upstream regulators of BCR signaling such as CD79A, commonly observed in other lymphomas, are rare in MCL. The transcription factor SOX11 is overexpressed in the majority (78% to 93%) of MCL patients and is considered an MCL-specific oncogene. So far, attempts to understand SOX11 function in vivo have been hampered by the lack of appropriate animal models, because germline deletion of SOX11 is embryonically lethal. We have developed a transgenic mouse model (Eμ-SOX11-EGFP) in the C57BL/6 background expressing murine SOX11 and EGFP under the control of a B-cell-specific IgH-Eμ enhancer. The overexpression of SOX11 exclusively in B cells exhibits oligoclonal B-cell hyperplasia in the spleen, bone marrow, and peripheral blood, with an immunophenotype (CD5CD19CD23) identical to human MCL. Furthermore, phosphocytometric time-of-flight analysis of the splenocytes from these mice shows hyperactivation of pBTK and other molecules in the BCR signaling pathway, and serial bone marrow transplant from transgenic donors produces lethality with decreasing latency. We report here that overexpression of SOX11 in B cells promotes BCR signaling and a disease phenotype that mimics human MCL.

Impact of Sox11 over-expression in Ba/F3 cells

“…10,11,16 Oncogenic transformation associated with increased BCR signaling has been reported in murine B-cells overexpressing Sox11. 9 While the pro-B cell line in the present study lack the BCR, Sox11 was nevertheless able to significantly alter the global gene …”

“…7,8 SOX11 overexpression has also been associated with increased B-cell receptor signaling and promotion of oncogenic transformation of B-cells in a murine model. 9 However, other studies report reduced cell proliferation upon SOX11 expression in MCL cells. 10,11 The non-malignant, IL-3 dependent pro-B cell line Ba/F3, which does not express immunoglobulins, 12 has previously been used for evaluating the transformation capability of potential oncogenes.…”

Increased tumour angiogenesis in SOX11‐positive mantle cell lymphoma

“…Previous studies have shown the expression of vascular endothelial growth factor (VEGF) mRNA and protein in a limited number of MCL, but its relation to SOX11 expression was not investigated . Interestingly, SOX11 expression seems to induce higher activation of BCR signalling in MCL . One of the downstream effects of BCR signalling in these tumours was an increased expression of VEGF .…”

“…The relevance of SOX11‐induced angiogenesis and PDGFA in the progression of the tumours was highlighted by the inhibition of tumour growth in animal models treated with the inhibitor of the PDGFA pathway imatinib . The biological differences between SOX11‐positive and ‐negative MCL include a large number of pathways and genetic alterations that may also influence angiogenesis and other relevant mechanisms . The more aggressive behaviour of the tumours may result from the integrative contribution of these mechanisms.…”

“…The oncogenic potential of SOX11 in MCL has been demonstrated in xenograft models, but the full mechanisms involved in promoting its function are still not well understood. 9,10 Recent studies have shown that SOX11 may contribute to the pathogenesis of MCL by blocking the B cell differentiation process, increasing the B cell receptor signalling and promoting tumour cell-microenvironment interactions that facilitate tumour growth and dissemination, 11,12 Gene expression profiling studies of SOX11positive and negative MCL cell lines and xenotransplanted tumours derived from these cell lines have shown that SOX11 expression is associated with a significant enrichment of gene signatures related to tumour angiogenesis. SOX11-positive tumours also had a significant increased expression of different proangiogenic factors compared to SOX11-knockdown tumours and displayed an enhanced microvascular network.…”