SOX11 nuclear protein was detected in 50 cases (93%) of conventional mantle cell lymphoma and also in the 12 cyclin D1-negative cases of mantle cell lymphoma, the six cases of lymphoblastic lymphomas, in two of eight cases of Burkitt's lymphoma, and in two of three T-prolymphocytic leukemias but was negative in the remaining lymphoid neoplasms.
SOX11-positive MCL showed a significant higher microvascular development than negative tumours (median MVA = 14.5 × 10<sup>-3</sup> versus 5.0 × 10<sup>-3</sup> P < 0.001; median MVD = 18.6/μm<sup>2</sup> versus 14.2/μm<sup>2</sup> , P = 0.021).
An integrative epigenomic approach revealed 10,504 differentially methylated regions in regulatory elements marked by H3K27ac in MCL primary cases, including a distant enhancer showing de novo looping to the MCL oncogene SOX11.
Clinically, the nonnodal MCL subset is notable for leukemic presentation, indolent behavior, and association with hypermutated IGHV and lack of SOX11 expression, which differentiates it from the conventional nodal MCL.
Data showed the transcriptional levels of SOX11 and cyclin D1 were higher for the mantle cell lymphoma (MCL) samples compared with chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), hairy cell leukemia (HCL), splenic marginal zone lymphoma (SMZL), and healthy collators.
Heterogeneity in the clinical course of MCL-indolent vs aggressive-is further delineated by a correlation with the mutational status of the variable region of immunoglobulin heavy chain, methylation status, and SOX-11 expression.
However, recent data show that the neural transcription factor SOX11 is a disease defining antigen and several involved signaling pathways have been pin-pointed, among others the Wnt/β-catenin pathway that is of importance for proliferation in MCL.
In conclusion, we defined nonnodal presentation, predominantly hypermutated IGVH, lack of genomic complexity, and absence of SOX11 expression as qualities of a specific subtype of iMCL with excellent outcomes that might be managed more conservatively than cMCL.
In intravenous MCL xenograft models, SOX11<sup>+</sup> MCL cells display higher cell migration, invasion, and growth compared with SOX11-knockdown cells, and specific FAK and CXCR4 inhibitors impair SOX11-enhanced MCL engraftment in bone marrow.
In such cases, the transcription factor SOX11 represents an important diagnostic marker, as it is expressed in most MCLs and, in particular, in all cyclin D1-negative MCLs reported so far.
In summary, SOX11-negative MCL is characterized by more frequent leukemic non-nodal disease, classic morphology, more frequent expression of CD23 and CD200, and a lower Ki67 index.
In this issue of Blood, Salaverria et al report that more than half of Cyclin D1- (CCND1) negative SOX11-positive mantle cell lymphoma (MCL) had CCND2 gene rearrangement predominantly with immunoglobulin (IG) light chain genes.(1)
Interestingly, our data revealed a potential inverse relationship between phosphorylated Y705 STAT3 and SOX11 expression in MCL cell lines, primary tumors, and patient-derived xenografts.