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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

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′-IndexTermCTTCTCCGACCTGGTGTTCACA-3′ and SOX11-A: 5′-IndexTermCCCTCCACCCTACCACCG-3′. Detection probes were as follows: SOX11-FL: 5′-IndexTermTCACCACTACAACTTCCTCCCAAGGAACCC-FL and SOX11-LC640: LC640-IndexTermGCTCTGCACCCTCCGAGAGAAAGAGCGA-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.

In the total cohort, elevated SOX11 expression was present in 95/219 cases (43%) and was strongly associated with a t(11;14) translocation (84/100, 84% in t(11;14)-positive cases versus 11/119, 9% in t(11;14)-negative cases, P<0.001). Correspondingly, SOX11 expression was more frequent in CCND1-expressing cases in comparison to CCND1-negative cases (85/108 (79%) in CCND1-positive cases versus 10/111 (9%) in CCND1-negative cases, P<0.001) (Table 1). Also the absolute expression levels of both genes showed a high correlation (Spearman correlation coefficient: 0.587, P<0.001; Figure 1a). SOX11-positive patients were younger (66.1 versus 70.0 years; P=0.007), showed a slightly lower hemoglobin level (12.0 versus 13.5 g/dl; P=0.007) and a lower platelet count (145 000 versus 184 000/μl; P<0.001). Details are given in Table 1. A detailed analysis within the respective diagnostic subgroups revealed that SOX11 was expressed in 84/100 (84%) t(11;14)-positive MCL cases with an overall high-expression level (median: 49.9; range: 0.3–1063.8). As expected in this entity, all cases were CCND1-positive. The resulting amount of 16% CCND1+/SOX11− cases is slightly higher but in line with the reported 7–13%.4, 9, 10, 11 In the group of 49 t(11;14)-negative mature B-cell neoplasms with an MCL-typical immunophenotype, 9 cases (total 9/49, 18%) showed a SOX11 expression (median: 1.7; range: 0.4–322.7), suggesting that these 9 cases might be considered t(11;14)-negative MCLs. In three of these nine cases, histology information was available and confirmed a MCL-typical histology, why we included these three cases as t(11;14)-negative MCLs. Two of the 40 CLL/PL cases were SOX11-positive but lacked t(11;14) and CCND1 expression; however, these patients are clearly diagnosed as CLL/PL by immunophenotyping and did not show a MCL-typical immunophenotype. In contrast, SOX11 was never rated positive in classical CLL cases, whereas one case showed high CCND1 expression, although t(11;14) negative (see Table 1). The mutational status of IGHV was analyzed in a subgroup of patients (n=112), including MCL (n=60), CLL/PL (n=29) and CLL (n=23) patients, and was compared to public databases (IMGT/V-QUEST; http://www.imgt.org). There was no significant correlation of the IGHV mutational status with SOX11 expression (26 unmutated and 35 mutated IGHV within SOX11-negative cases versus 30 unmutated and 25 mutated cases in SOX11-expressing patients) (Table 1). This was more prominently reflected in MCL, where SOX11-negative patients showed more often a hypermutated IGHV than SOX11-expressing patients (10/15, 67% in SOX11− versus 30/74, 41% in SOX11+; P=0.088). CD23 is an IgE Fc receptor and a marker for activated B cells, but not or weakly expressed on resting mature B cells. Among mature B-cell neoplasms, its expression is useful for distinguishing CLL and MCL cases. However, a small subset of MCL cases show CD23 expression.12 We correlated the CD23 expression (% positive cells) with SOX11 expression, but no correlation was detectable (59% CD23+ cells in SOX11− patients versus 60% in SOX11+ patients). For a total of 107 patients the time-to-treatment (TTT) was available. In the total cohort, cases with SOX11 expression had a shorter TTT as compared with those without (median TTT: 37 versus 56 months, P=0.011), this was also true for CCND1-positive (median TTT: 37 versus 58 months, P=0.07) and t(11;14)-positive cases (median TTT: 6 versus 56 months, P=0.003), probably reflecting the indication for therapy by diagnosis of MCL due to its aggressive behavior (Figure 1b). Small case numbers of SOX11− and SOX11+ patients within the four analyzed diagnostic subgroups allowed no valid analysis within the individual groups. However, separate analysis of MCLs (t(11;14)-positive and -negative) revealed that SOX11-positive patients showed a more indolent course compared with SOX11-negative MCLs (37 versus 4.5 months, P=n.s.) (Figure 1b). Further, SOX11+/t(11;14)− cases showed a more adverse prognosis than SOX11+/t(11;14)+ MCL patients; however, follow-up data was only available for three of these nine t(11;14)−/SOX11+ patients (median TTT SOX11+/t(11;14)−: 1.3 versus 37 months in SOX11+/t(11;14)+ cases; P=n.s.). In agreement with our findings, Wang et al.10 and Nygren et al.12 showed a shorter overall survival (OS) of 16 and 18 months of SOX11-negative MCL patients in contrast to 49 and 38 months in SOX11-expressing MCL patients. In contrast, Fernandez et al.11 analyzed 112 MCL cases and reported a better 5-year OS of SOX11-negative MCL patients of 78% in contrast to SOX11-positive patients (36%) and therefore, defined beside other markers, the absence of SOX11 as a marker for the indolent MCL subtype. This furthermore illustrates the controversial discussion regarding the prognostic impact of SOX11 expression in MCL, which may be due to low case numbers of SOX11− cases in all studies.

Table 1 Clinical and genetic parameters and the distribution within the four analyzed entities are given for SOX11+ and SOX11− cases
Figure 1
figure1

Correlation of SOX11 and CCND1 expression levels (a) and TTT analyses (b). (a) Box plots showing the median expression levels of SOX11 and CCND1 in SOX11-negative (upper panel) and -positive cases (lower panel). Case numbers of CCND1-positive and -negative cases are given beneath in tables. (b) Kaplan–Meier plots showing the TTT according to SOX11 expression status (left graph) and t(11;14) status (middle graph) in the total cohort, and SOX11 expression status in MCL (right graph).

Summarized, some rare mature B-cell neoplasms are considered to belong to the MCL entity but lack the t(11;14) and CCND1 overexpression. The differential diagnosis of this entity from other mature B-cell neoplasms is difficult. SOX11 expression may be considered as a useful marker in addition to CCND1 expression in t(11;14)-negative MCL, as the only missing hallmark of these MCL cases is a t(11;14). Overall, patients with SOX11 expression showed a shorter TTT and SOX11-expressing MCL patients showed probably a more indolent course, but further analyses within a larger cohort are warranted to prove the independent diagnostic role of SOX11 expression as well as its prognostic impact.

References

  1. 1

    Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th edn. International Agency for Research on Cancer IARC: Lyon, 2008.

    Google Scholar 

  2. 2

    Jares P, Colomer D, Campo E . Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics. Nat Rev Cancer 2007; 7: 750–762.

    CAS  Article  Google Scholar 

  3. 3

    Fu K, Weisenburger DD, Greiner TC, Dave S, Wright G, Rosenwald A et al. Cyclin D1-negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling. Blood 2005; 106: 4315–4321.

    CAS  Article  Google Scholar 

  4. 4

    Mozos A, Royo C, Hartmann E, de JD, Baro C, Valera A et al. SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype. Haematologica 2009; 94: 1555–1562.

    CAS  Article  Google Scholar 

  5. 5

    Xu W, Li JY . SOX11 expression in mantle cell lymphoma. Leuk Lymphoma 2010; 51: 1962–1967.

    CAS  Article  Google Scholar 

  6. 6

    Dreyling M, Kluin-Nelemans HC, Bea S, Klapper W, Vogt N, fau-Larue MH et al. Update on the molecular pathogenesis and clinical treatment of mantle cell lymphoma: report of the 11th Annual Conference of the European Mantle Cell Lymphoma Network. Leuk Lymphoma 2013; 54: 699–707.

    CAS  Article  Google Scholar 

  7. 7

    Bhattaram P, Penzo-Mendez A, Sock E, Colmenares C, Kaneko KJ, Vassilev A et al. Organogenesis relies on SoxC transcription factors for the survival of neural and mesenchymal progenitors. Nat Commun 2010; 1: 9.

    Article  Google Scholar 

  8. 8

    Lefebvre V, Dumitriu B, Penzo-Mendez A, Han Y, Pallavi B . Control of cell fate and differentiation by Sry-related high-mobility-group box (Sox) transcription factors. Int J Biochem Cell Biol 2007; 39: 2195–2214.

    CAS  Article  Google Scholar 

  9. 9

    Ek S, Dictor M, Jerkeman M, Jirstrom K, Borrebaeck CA . Nuclear expression of the non B-cell lineage Sox11 transcription factor identifies mantle cell lymphoma. Blood 2008; 111: 800–805.

    CAS  Article  Google Scholar 

  10. 10

    Wang X, Asplund AC, Porwit A, Flygare J, Smith CI, Christensson B et al. The subcellular Sox11 distribution pattern identifies subsets of mantle cell lymphoma: correlation to overall survival. Br J Haematol 2008; 143: 248–252.

    Article  Google Scholar 

  11. 11

    Fernandez V, Salamero O, Espinet B, Sole F, Royo C, Navarro A et al. Genomic and gene expression profiling defines indolent forms of mantle cell lymphoma. Cancer Res 2010; 70: 1408–1418.

    CAS  Article  Google Scholar 

  12. 12

    Nygren L, Baumgartner WS, Klimkowska M, Christensson B, Kimby E, Sander B . Prognostic role of SOX11 in a population-based cohort of mantle cell lymphoma. Blood 2012; 119: 4215–4223.

    CAS  Article  Google Scholar 

  13. 13

    Ondrejka SL, Lai R, Smith SD, Hsi ED . Indolent mantle cell leukemia: a clinicopathological variant characterized by isolated lymphocytosis, interstitial bone marrow involvement, kappa light chain restriction, and good prognosis. Haematologica 2011; 96: 1121–1127.

    Article  Google Scholar 

  14. 14

    Swerdlow SH, Williams ME . From centrocytic to mantle cell lymphoma: a clinicopathologic and molecular review of 3 decades. Hum Pathol 2002; 33: 7–20.

    CAS  Article  Google Scholar 

  15. 15

    Bacher U, Kern W, Haferlach C, Alpermann T, Haferlach T, Schnittger S . Cyclin D1 (CCND1) mRNA expression assessed by real-time PCR is increased in patients with mantle cell lymphoma and contributes to diagnosis in B-cell lymphoma cases. Blood 2013; 120: 1595a.

    Google Scholar 

Download references

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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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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