SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype

Abstract

Background: Cyclin D1-negative mantle cell lymphoma is difficult to distinguish from other small B-cell lymphomas. The clinical and pathological characteristics of patients with this form of lymphoma have not been well defined. Overexpression of the transcription factor SOX11 has been observed in conventional mantle cell lymphoma. The aim of this study was to determine whether this gene is expressed in cyclin D1-negative mantle cell lymphoma and whether its detection may be useful to identify these tumors.

Design and methods: The microarray database of 238 mature B-cell neoplasms was re-examined. SOX11 protein expression was investigated immunohistochemically in 12 cases of cyclin D1-negative mantle cell lymphoma, 54 cases of conventional mantle cell lymphoma, and 209 additional lymphoid neoplasms.

Results: SOX11 mRNA was highly expressed in conventional and cyclin D1-negative mantle cell lymphoma and in 33% of the cases of Burkitt's lymphoma but not in any other mature lymphoid neoplasm. 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. Cyclin D2 and D3 mRNA levels were significantly higher in cyclin D1-negative mantle cell lymphoma than in conventional mantle cell lymphoma but the protein expression was not discriminative. The clinico-pathological features and outcomes of the patients with cyclin D1-negative mantle cell lymphoma identified by SOX11 expression were similar to those of patients with conventional mantle cell lymphoma.

Conclusions: SOX11 mRNA and nuclear protein expression is a highly specific marker for both cyclin D1-positive and negative mantle cell lymphoma.

Figure 1.

Heat map representing gene expression values for SOX11, CYCLIN D1 (CCND1), CYCLIN D2 (CCND2) AND CYCLIN D3 (CCND3). Cases of MCL, including CCND1-negative MCL are shown in the top half whereas other lymphoid neoplasms are displayed in the bottom half.

Figure 2.

Quantitative RT-PCR analysis of SOX11 mRNA expression in mantle cell lymphoma (MCL), Burkitt’s lymphoma (BL) and other lymphoid neoplasms (Other).

Figure 3.

SOX11 protein expression in conventional and cyclin D1-negative MCL. (A, D) Conventional and cyclin D1-negative MCL, respectively (Hematoxilin & Eosin; x400); (B, E) Cyclin D1 and (C, F) SOX11 expression in conventional and cyclin D1-negative MCL, respectively (immunohistochemistry; x200);

Figure 4.

Nuclear SOX11 staining is observed in Burkitt’s lymphoma and T-cell prolymphocytic lymphoma but staining is only cytoplasmic in follicular lymphoma and diffuse large B-cell lymphoma. (A,B) Burkitt’s lymphoma; (C,D) T-cell prolymphocytic lymphoma; (E,F) follicular lymphoma; (G,H) diffuse large B-cell lymphoma.

Figure 5.

FISH analysis on cyclin D1-negative MCL. (A) CCND1 break-apart probe showing two fusion signals in each cell; (B) CCND2 probe showing a split signal pattern suggesting a rearrangement of the gene.

Figure 6.

Cyclin D2 protein expression in conventional and cyclin D1-negative MCL and in various lymphoid neoplasms. (A,B) conventional MCL; (C,D) cyclin D1-negative MCL; (E,F) small lymphocytic lymphoma; (G,H) follicular lymphoma; (I,J) splenic marginal zone lymphoma.