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SOX11 overexpression is a specific marker for mantle cell lymphoma and correlates with t(11;14) translocation, CCND1 expression and an adverse prognosis

Leukemia volume 27, pages 2388–2391 (2013)Cite this article

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According to the WHO classification, B-cell lymphomas can be divided in several subgroups depending on their morphological and phenotypic properties.1 Mantle cell lymphoma (MCL) accounts for 5–10% of mature B-cell neoplasms and are believed to derive from naive B cells. MCL are usually positive for CD5, CD20 and CD43, but are negative for CD10 and BCL6. CD23 is negative or weakly expressed.1 Diagnosis of MCL is based on cytomorphology, histology, immunophenotype as well as presence of a t(11;14)(q13;q32)/IGH-CCND1 rearrangement or demonstration of cyclin D1 (CCND1) overexpression.2 However, some cases that are considered by expression profiling or immunophenotyping to belong to the MCL entity lack the t(11;14) translocation and the CCND1 overexpression and thus are difficult to distinguish from other mature B-cell neoplasms.3, 4 This distinction is clinically very relevant as true MCLs show an aggressive behavior, whereas many other B-cell lymphomas do not. MCL usually shows a rapid clinical evolution, poor response to conventional therapeutic regimes, frequent relapses and a median survival of 3–4 years.5 Fortunately, new therapies seem to significantly improve the progression-free survival.6 SOX11 is a neural transcription factor involved in tissue remodeling in embryogenesis.7, 8 The overexpression of SOX11 has been demonstrated to be specific for MCL independent of CCND1 positivity, suggesting a diagnostic role of SOX11 expression in t(11;14)-negative MCLs.4, 9, 10 SOX11 is not expressed in other lymphoid neoplasms, with the exception of lymphoblastic lymphoma, some Burkitt lymphomas and T-prolymphocytic leukemia, which are readily discriminated from MCL by standard diagnostics.4 The prognostic role of SOX11 expression has been controversially discussed.10, 11, 12, 13 Recently, some studies have identified a group of MCL patients with an indolent clinical course and a long survival.14 Subsequently, the absence of SOX11 expression was described as diagnostic marker of these indolent MCLs.11 In this study, we evaluated the applicability and usefulness of SOX11 expression as a diagnostic marker for differentiation of mature B-cell neoplasms and to determine its impact on outcome.

We analyzed 219 patients with mature B-cell neoplasms that were diagnosed by cytomorphology, immunophenotyping, cytogenetics and fluorescence in situ hybridization, and based on these methods categorized into t(11;14)-positive MCL (n=100), t(11;14)-negative mature B-cell neoplasms with a MCL-typical immunophenotype (n=49), chronic lymphocytic/prolymphocytic leukemia (CLL/PL, n=40) and CLL (n=30). The study design adhered to the tenets of the Declaration of Helsinki and was approved by our institutional review board before its initiation. Expression levels of SOX11 were analyzed by quantitative real time PCR using the LightCycler 480 System (Roche, Mannheim, Germany). Amplification was performed with the following primers: SOX11-S: 5′-CTTCTCCGACCTGGTGTTCACA-3′ and SOX11-A: 5′-CCCTCCACCCTACCACCG-3′. Detection probes were as follows: SOX11-FL: 5′-TCACCACTACAACTTCCTCCCAAGGAACCC-FL and SOX11-LC640: LC640-GCTCTGCACCCTCCGAGAGAAAGAGCGA-Pho. CCND1 was analyzed as described before.15 The gene expression levels were quantified using reference plasmid DNA containing SOX11 or ABL1 sequences, and are given relative to the expression of the housekeeping gene ABL1. Based on a negative control cohort (n=40) comprising 21 peripheral blood (PB) and 19 bone marrow (BM) samples without evidence for malignancy the cutoff for rating the expression ratio positive was calculated by the mean value plus the threefold s.d. and resulted in 0.28 in PB and 0.29 in BM for SOX11.

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Acknowledgements

We thank all clinicians for sending samples to our laboratory for diagnostic purposes and for providing clinical information and follow-up data. In addition, we thank all the co-workers at the MLL Munich Leukemia Laboratory for approaching together many aspects in the field of leukemia diagnostics and research. Especially, the technical assistance of Antje Stiel and Jessica Brust, who contributed to SOX11 qRT-PCR and IGHV mutational analyses, is greatly appreciated. In addition, we are grateful for the data management support performed by Tamara Alpermann.

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  1. MLL Munich Leukemia Laboratory GmbH, Munich, Germany

    M Meggendorfer, W Kern, C Haferlach, T Haferlach & S Schnittger

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Correspondence to S Schnittger.

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WK, CH, TH and SS have equity ownership of MLL Munich Leukemia Laboratory GmbH. MM is employed by MLL Munich Leukemia Laboratory GmbH.

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Meggendorfer, M., Kern, W., Haferlach, C. et al. SOX11 overexpression is a specific marker for mantle cell lymphoma and correlates with t(11;14) translocation, CCND1 expression and an adverse prognosis. Leukemia 27, 2388–2391 (2013). https://doi.org/10.1038/leu.2013.141

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