LYMPHOID NEOPLASIA SOX 11 promotes tumor angiogenesis through transcriptional regulation of PDGFA in mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasia derived from mature B cells genetically characterized by the presence of the t(11;14)(q13;q32) translocation causing cyclin D1 overexpression. Furthermore, other secondary genetic alterations also contribute to the development and aggressiveness of MCL. However, recent studies have identifieda subset ofMCLwith indolent clinical behavior that tends to present with leukemic disease instead of extensive nodal infiltration and patients may not need chemotherapy for long periods. Recently, molecular studies have identified SOX11 (SRY [sex determining region-Y]-box11), as one of the best characterized discriminatory genes between these 2 clinical subtypes of MCL tumors. SOX11, togetherwith SOX4 and SOX12, belongs to the subgroupC of the SOX gene family encoding for transcription factors which play a critical role in embryonic development and cell differentiation. SOX11 plays an important role in the regulation of neuronal cell survival and neurite growth, and is highly expressed in different central nervous systemmalignancies, solid tumors, aggressiveMCL, and at lower levels in a subgroup of Burkitt and lymphoblastic lymphomas. However, the oncogenic mechanisms of SOX11 contributing to the development and progression of these tumors are largely unknown. We have recently demonstrated the in vivo tumorigenic potential of SOX11 in a MCL xenograft model. SOX11 blocks the terminal B-cell differentiation through direct positive regulation of PAX5 but the specific mechanisms regulated by SOX11 promoting the oncogenic and rapid tumor growth of aggressiveMCL still remain to be elucidated. To further characterize the potential oncogenic mechanisms regulated by SOX11 in MCL, we have investigated the gene and protein expression profiling of SOX11-positive and -knockdown MCL xenograft tumors, cell lines, and primary SOX11-positive and SOX11-negativeMCL.We have identified that SOX11modulates angiogenesis in MCL, and this mechanism is mediated by the upregulation of several proangiogencic factors, principally platelet-derived growth factor A (PDGFA). The inhibition of the PDGFA pathway not only impairs angiogenic development both in vitro and in vivo but also MCL tumor growth in vivo, offering a promising novel therapeutic strategy for the treatment of aggressive MCL.