SOX11

SOX11 (SOX = SRY-related HMG box) is a nuclear transcription factor belonging to subgroup C of SRY (sex determining region on Y-chromosome) related HMG (high mobility group) box genes. Subgroup C has 3 members: SOX4, SOX11 and SOX12. The human SOX11 is mapped to chromosome 2p25.3. The human SOX11 protein is 46.7 kDa and has 441 amino acids. It contains 2 functional domains: A HMG box DNA-binding domain, located at the N-terminus, and a transactivation domain (TAD), located at the C-terminus (10-11). Within the subgroup, SOX11 is homologous to SOX4 with 55% amino acid identity with the C-terminal TAD and 86% amino acid identity for the N-terminal HMG domain.
The SOX genes are co-expressed in embryonic neuronal progenitor cells and the mesenchymal cells in many developing organs. SOX11 expression is critical for embryonic neurogenesis and tissue remodeling, is normally expressed during the developing nervous system of human embryos and is required for neurite growth and neuron survival. Expression is seen in fetal tissues (18-25 weeks) mainly in the brain. In situ hybridization shows expression throughout the central nervous system (CNS) from earliest stage studied (3.5 weeks) to older fetuses (19 weeks). Outside the CNS SOX11 seems primarily to be expressed at sites of epithelial-mesenchymal interactions. SOX11 is not expressed in normal adult human tissues. The role of SOX 11 in lymphopoiesis remains to be elucidated and hitherto, SOX 4 is the only gene in the SOX family that is found to have an important role in early B- and T-cell development.
The tissue and development restricted expression makes SOX11 a potentially important diagnostic tool in immunohistochemistry (IHC).

SOX11 over-expression is reported in over 90% of mantle cell lymphomas (MCL), including the rare cyclin D1 negative cases. Strong expression of SOX11 is also seen in most cases of B-and T-lymphoblastic leukemias/ lymphomas and half of cases of childhood Burkitt lymphoma. SOX11 is weakly expressed in some cases of hairy cell leukemia (HCL). One study demonstrated intense nuclear staining for SOX11 in 5 out of 10 cases of HCL but no nuclear staining was in 30 cases of plasma cell myelomas of which 12 cases had t(11:14)(1) - the same translocation as seen in MCL. One recent study on monoclonal antibodies has shown SOX11 positive case of DLCBCL (4%) and MZL (4%).
SOX11 is coexpressed with SOX4 in cases of malignant glioma and medulloblastoma. SOX11 expression has been proposed to be associated with improved survival among high grade epithelial ovarian cancers.

Currently the only diagnostic application is verification of mantle cell lymphomas, particularly the rare cyclin D1 negative cases.

At present, no accessible normal tissue expressing SOX11 has been identified and mantle cell lymphoma seems to be the preferred recommendable positive tissue control.The vast majority of neoplastic cells must show an as strong as possible nuclear staining reaction (a minimal cytoplasmic staining reaction must be accepted), while other cells must be negative. In addition tonsil can be used as negative tissue control, in which no nuclear staining reaction must be seen. A weak diffuse background staining can be expected.

Chen Y-H, Gao J, Fan G, Peterson LC. Nuclear expression of sox11 is highly associated with mantle cell lymphoma but is independent of t(11;14)(q13;q32) in non-mantle cell B-cell neoplasms. Mod. Pathol. 2010;23(1):105–12. Dictor M, Ek S, Sundberg M, et al. Strong lymphoid nuclear expression of SOX11 transcription factor defines lymphoblastic neoplasms, mantle cell lymphoma and Burkitt’s lymphoma. Haematologica. 2009;94(11):1563–8. Ek S, Dictor M, Jerkeman M, Jirström K, Borrebaeck C a K. Nuclear expression of the non B-cell lineage Sox11 transcription factor identifies mantle cell lymphoma. Blood. 2008; Hargrave M, Wright E, Kun J, Emery J, Cooper L, Koopman P. Expression of the Sox11 gene in mouse embryos suggests roles in neuronal maturation and epithelio-mesenchymal induction. Dev. Dyn. 1997;210(2):79–86. Jay P, Gozé C, Marsollier C, et al. The human SOX11 gene: cloning, chromosomal assignment and tissue expression. Genomics. 1995;29(2):541–545 Lee CJ, Appleby VJ, Orme AT, Chan WI, Scotting PJ. Differential expression of SOX4 and SOX11 in medulloblastoma. J Neurooncol 2002;57:201–214. Megan O. Nakashima, et al. Utility and Diagnostic Pitfalls of SOX11 Monoclonal Antibodies in Mantle Cell Lymphoma and other Lymphoproliferative Disorders. Appl Immunohistochem Mol Morphol 2014;22:720–727. Mozos A, Royo C, Hartmann E, et al. SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype. Haematologica. 2009;94(11):1555–1562. Nordström L, Andréasson U, Jerkeman M, Dictor M, Borrebaeck C, Ek S. Expanded clinical and experimental use of SOX11 - using a monoclonal antibody. BMC Cancer. 2012;12(1):269. Penzo-Méndez A. Critical roles for SoxC transcription factors in development and cancer. Int. J. Biochem. Cell Biol. 2010;42(3):425–8. Sernbo S, Gustavsson E, Brennan DJ, et al. The tumour suppressor SOX11 is associated with improved survival among high grade epithelial ovarian cancers and is regulated by reversible promoter methylation. BMC Cancer. 2011;11(1):405. Soldini D, Valera A, Sole C, et al. Assessment of SOX11 Expression in Routine Lymphoma Tissue Sections of Mantle Cell Lymphoma. 2013;00(00):1–8. Wang X, Asplund a C, Porwit A, et al. The subcellular Sox11 distribution pattern identifies subsets of mantle cell lymphoma: correlation to overall survival. Br. J. Haematol. 2008;143(2):248–52. Wegner M. From head to toes: the multiple facets of Sox proteins. Nucleic Acids Res. 1999;27(6):1409–20. Weigle B, Ebner R, Temme A, et al. Highly specific overexpression of the transcription factor SOX11 in human malignant gliomas. Oncol Rep 2005;13:139–14 Wetering M Van De, Oosterwegel M, Norren K Van, Clevers H. Sox-4 , an Sry-like HMG box protein , is transcriptional activator in lymphocytes. EMBO J. 1993 Oct; 12(10): 3847–3854. Zeng W, Fu K, Quintanilla-Fend L, Lim M, Ondrejka S, Hsi ED. Cyclin D1-negative Blastoid Mantle Cell Lymphoma Identified by SOX11 Expression. Am. J. Surg. Pathol. 2012;36(2):214–219