Nuclear expression of the non–B-cell lineage Sox11 transcription factor identifies mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL) is defined pathologically by the detection of CD20, CD5, and most importantly cyclin D1 (CCND1). Its distinction from other lymphomas is important for prognosis and appropriate therapy, but occasional cases may fail to express CCND1 and morphologic simulators may express CD20 and CD5 but not CD23. In this study, we show that the transcription factor Sox11 is specifically expressed in the nucleus of MCL compared with other lymphomas and benign lymphoid tissue. Although the role of Sox11 presently is not known in lymphocyte ontogeny, it is normally expressed in the developing central nervous system in the embryo and shows sequence homology with Sox4, a transcription factor crucial for B lymphopoiesis. Sox11 mRNA is increased in gliomas compared with healthy brain tissue, suggesting a role in malignant transformation and/or cell survival. Our novel finding of specific overexpression of Sox11 mRNA and nuclear protein in both cyclin D1-positive and -negative MCL may be useful for the diagnosis of MCL as a complement to cyclin D1 and also suggests a functional role for Sox11 in MCL. IntroductionB-cell lymphomas (BCLs) are divided into several subgroups depending on their morphologic and phenotypic properties, 1 and accurate diagnosis is necessary for prognosis and targeted therapy. Mantle cell lymphoma (MCL) accounts for 5% to 10% of BCLs and is characterized by overexpression of cyclin D1 (CCND1) due to the specific translocation t(11;14)(q13;q32), which brings the cyclin D1 (BCL1/CCND1) gene under the control of the immunoglobulin heavy chain enhancer. MCL may be distinguished from potential morphologic mimics, including chronic lymphocytic leukemia/small cell lymphoma (CLL), follicular lymphoma (FL), and marginal zone lymphoma (MZL) based on immunohistochemical staining (IHC) for CD5, CD23, and CD10. MCL and CLL both express CD5 but MCL, in contrast to CLL, generally lacks CD23 by immunohistochemistry. FL lacks both CD5 and CD23 but most often expresses CD10, whereas MZL is typically negative for all 3 antigens. Nevertheless, cases of CD23 Ϫ CLL occur and rare instances of CD5 ϩ MZL have been described. Follicular dendritic cell networks are characteristically expanded in MCL, but this occurs also in FL and MZL. CCND1 overexpression is thus the hallmark of MCL even though approximately 10% of MCLs lack CCND1 expression and may be misdiagnosed by overreliance on CCND1 IHC. 2,3 For these reasons, fluorescence in situ hybridization (FISH) targeting the specific translocation probably affords the most sensitive detection of MCL, although it is not widely performed and the results may be more easily affected by technical factors than modern IHC. Thus, specific markers that can aid in stratification and diagnosis of lymphomas in general and MCL in particular would be of major interest.In this study, we demonstrate that the transcription factor Sox11 is specifically up-regulated in MCL and distinguishes MCL from other B-cell lymphomas. Sox11 belongs to the Sox gene family and is mapped to chrom...

Incidence of preclinical manifestations of mantle cell lymphoma and mantle cell lymphoma in situ in reactive lymphoid tissues

“…16,17 Among non-Hodgkin lymphomas, only lymphoblastic lymphomas and Burkitt lymphomas can also express SOX11. 18 Of interest, in a recent report, lack of SOX11 has been identified by gene expression profiling in a subgroup of mantle cell lymphoma cases that showed indolent behaviour with long-term survival even without treatment, common leukemic presentation and splenomegaly, as well as a predominance of mutated immunoglobulin heavy chain genes and low levels of secondary genetic aberrations.…”

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

“…[3][4][5] Recently, sox11, a transcription factor involved in embryonic neurogenesis and tissue remodeling, has been found to be expressed in the nuclei of mantle cell lymphoma cells. 6,7 This intriguing finding raises the question about the possible association between the nuclear expression of sox11 and t(11;14)(q13;q32). 6 The SRY (sex-determining region Y)-box11 (SOX11) gene is mapped to chromosome 2p25 and belongs to the SRY-related high mobility group (HMG) box (SOX) gene family characterized by containing the HMG domain with high identity to the HMG domain in SRY.…”

“…6,7 This intriguing finding raises the question about the possible association between the nuclear expression of sox11 and t(11;14)(q13;q32). 6 The SRY (sex-determining region Y)-box11 (SOX11) gene is mapped to chromosome 2p25 and belongs to the SRY-related high mobility group (HMG) box (SOX) gene family characterized by containing the HMG domain with high identity to the HMG domain in SRY. 8 More than 20 SOX genes have been identified in humans and mice, and are divided into 8 groups according to the degree of homology within and outside the HMG domain.…”

Whole genome profiling and other high throughput technologies in lymphoid neoplasms—current contributions and future hopes

“…46 SOX11 overexpression was found as a relatively specific feature of MCL since it was detected in virtually all MCL but absent in other mature B-cell lymphomas with the exception of some BL. 69,70 SOX11 was also expressed in cyclin D1-negative MCL and therefore it is a good biomarker for the diagnosis of this variant. 70 SOX11 was also an element of the gene signature distinguishing conventional MCL from a subgroup of MCL with a very indolent clinical behavior, since it was negative in these latter tumors.…”