Advertisement

Tumor Biology

, Volume 36, Issue 6, pp 4433–4440 | Cite as

SOX11 expression in chronic lymphocytic leukemia correlates with adverse prognostic markers

  • Alejandro Roisman
  • Carmen Stanganelli
  • Virginia Palau Nagore
  • Guillermo Videla Richardson
  • María Elida Scassa
  • Raimundo Fernando Bezares
  • María Cabrejo
  • Irma Slavutsky
Research Article

Abstract

The transcription factor SOX11 plays an important role in embryonic neurogenesis and tissue remodeling. Recent studies have shown aberrant expression of SOX11 in various types of aggressive B cell neoplasms. In this study, we have analyzed SOX11 transcription levels in 86 patients with diagnosis of chronic lymphocytic leukemia (CLL). Results were correlated with well-known prognostic factors such as immunoglobulin heavy chain variable (IGHV) gene mutational status, cytogenetics risk groups and clinicopathological characteristics of the disease. Overall, 35 % of cases showed SOX11 expression; meanwhile, the remaining 65 % lacked gene expression. The analysis taking into account the IGHV mutational status showed significant differences in SOX11 transcripts levels between mutated (0.004 ± 0.0001) and unmutated CLL patients (0.405 ± 0.011) (p < 0.0001), as well as a positive correlation between SOX11 mRNA expression and the percentage of IGHV homology (p = 0.0001). Furthermore, significantly lower SOX11 mRNA expression was detected in patients with deletion 13q14 as a single alteration (0.016 ± 0.008) than those observed in cases with deletions 11q/17p (0.35 ± 0.017) (p = 0.02). The correlation of gene expression with clinical evolution showed shorter treatment free survival (p = 0.043) and overall survival (p = 0.047) in SOX11 positive patients compared to SOX11 negative cases. Our findings show for the first time an association between SOX11 expression and some CLL poor prognostic factors. These results suggest SOX11 as a possible biomarker that adds new biological information that could contribute to a better understanding of this pathology.

Keywords

Chronic lymphocytic leukemia SOX11 Gene expression profile IGHV mutational status Molecular cytogenetics 

Notes

Acknowledgments

This work was supported by grants from the National Research Council (CONICET), the National Agency of Scientific and Technical Promotion (ANPCyT), and the ¨Alberto J. Roemmers¨ Foundation.

Conflicts of interest

None

Supplementary material

13277_2015_3083_Fig5_ESM.gif (63 kb)
Fig. S1

(GIF 63 kb)

13277_2015_3083_MOESM1_ESM.tif (214 kb)
High resolution image (TIFF 214 kb)

References

  1. 1.
    Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005;352:804–5.CrossRefPubMedGoogle Scholar
  2. 2.
    Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukaemia. Blood. 1999;94:1848–54.Google Scholar
  3. 3.
    Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukaemia. Blood. 1999;94:1840–7.Google Scholar
  4. 4.
    Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M, et al. ZAP-70 expression as a surrogate for immunoglobulin variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003;348:1764–75.Google Scholar
  5. 5.
    Kröber A, Seiler T, Benner A, Bullinger L, Brückle E, Lichter P, et al. VH mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood. 2002;100:1410–6.Google Scholar
  6. 6.
    Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910–6.Google Scholar
  7. 7.
    Lefebvre V, Dumitriu B, Penzo-Méndez A, Han Y, Pallavi B. Control of cell fate and differentiation by Sry-related highmobility-group box (Sox) transcription factors. Int J Biochem Cell Biol. 2007;39:2195–214.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Hargrave M, Wright E, Kun J, Emery J, Cooper L, Koopman P. Expression of the Sox11 gene in mouse embryos suggests roles in neuronal maturation and epithelio-mesenchymal induction. Dev Dyn. 1997;210:79–86.CrossRefPubMedGoogle Scholar
  9. 9.
    Sock E, Rettig SD, Enderich J, Bösl MR, Tamm ER, Wegner M. Gene targeting reveals a widespread role for the high-mobility-group transcription factor Sox11 in tissue remodeling. Mol Cell Biol. 2004;24:6635–44.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Bergsland M, Werme M, Malewicz M, Perlmann T, Muhr J. The establishment of neuronal properties is controlled by Sox4 and Sox11. Genes Dev. 2006;20:3475–86.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Dy P, Penzo-Méndez A, Wang H, Pedraza CE, Macklin WB, Lefebvre V. The three SoxC proteins—Sox4, Sox11 and Sox12—exhibit overlapping expression patterns and molecular properties. Nucleic Acids Res. 2008;36:3101–7.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Schilham MW, Oosterwegel MA, Moerer P, Ya J, de Boer PA, van de Wetering M, et al. Defects in cardiac outflow tract formation and pro-B-lymphocyte expansion in mice lacking Sox-4. Nature. 1996;380:711–4.Google Scholar
  13. 13.
    Brennan DJ, Ek S, Doyle E, Drew T, Foley M, Flannelly G, et al. The transcription factor Sox11 is a prognostic factor for improved recurrence-free survival in epithelial ovarian cancer. Eur J Cancer. 2009;45:1510–17.Google Scholar
  14. 14.
    Weigle B, Ebner R, Temme A, Schwind S, Schmitz M, Kiessling A, et al. Highly specific overexpression of the transcription factor SOX11 in human malignant gliomas. Oncol Rep. 2005;13:139–44.Google Scholar
  15. 15.
    Lee CJ, Appleby VJ, Orme AT, Chan WI, Scotting PJ. Differential expression of SOX4 and SOX11 in medulloblastoma. J Neurooncol. 2002;57:201–4.CrossRefPubMedGoogle Scholar
  16. 16.
    Ek S, Dictor M, Jerkeman M, Jirström K, Borrebaeck CA. Nuclear expression of the non-B-cell lineage Sox11 transcription factor identifies mantle cell lymphoma. Blood. 2008;111:800–5.CrossRefPubMedGoogle Scholar
  17. 17.
    Dictor M, Ek S, Sundberg M, Warenholt J, György C, Sernbo S, et al. Strong lymphoid nuclear expression of SOX11 transcription factor defines lymphoblastic neoplasms, mantle cell lymphoma and Burkitt’s lymphoma. Haematologica. 2009;94:1563–8.Google Scholar
  18. 18.
    Mozos A, Royo C, Hartmann E, De Jong D, Baró C, Valera A, et al. SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype. Haematologica. 2009;94:1555–62.Google Scholar
  19. 19.
    Meggendorfer M, Kern W, Haferlach C, Haferlach T, Schnittger S. SOX11 overexpression is a specific marker for mantle cell lymphoma and correlates with t(11;14) translocation, CCND1 expression and an adverse prognosis. Leukemia. 2013;27:2388–91.CrossRefPubMedGoogle Scholar
  20. 20.
    Cao X, Fan L, Fang C, Zhu DX, Dong HJ, Wang DM, et al. The expression of SOX11, cyclin D1, cyclin D2, and cyclin D3 in B-cell lymphocytic proliferative diseases. Med Oncol. 2012;29:1190–6.Google Scholar
  21. 21.
    Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111:5446–56.Google Scholar
  22. 22.
    Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46:219–34.PubMedGoogle Scholar
  23. 23.
    Stanganelli C, Travella A, Bezares R, Slavutsky I. Immunoglobulin gene rearrangements and mutational status in Argentinian patients with chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk. 2013;13:447–57.CrossRefPubMedGoogle Scholar
  24. 24.
    Pritsch O, Magnac C, Dumas G, Egile C, Dighiero GV. Gene usage by seven hybrids derived from CD5+ B-cell chronic lymphocytic leukemia and displaying autoantibody activity. Blood. 1993;82:3103–12.PubMedGoogle Scholar
  25. 25.
    Campbell MJ, Zelenetz AD, Levy S, Levy R. Use of family specific leader region primers for PCR amplification of the human heavy chain variable region repertoire. Mol Immunol. 1992;29:193–203.CrossRefPubMedGoogle Scholar
  26. 26.
    Brochet X, Lefranc MP, Giudicelli V. MGT/V-QUEST: the highly customized and integrated system for IG and TR standardized V-J and V-D-J sequence analysis. Nucleic Acids Res. 2008;36:503–8.CrossRefGoogle Scholar
  27. 27.
    Ghia P, Stamatopoulus K, Belessi C, Moreno C, Stella S, Guida G, et al. Geographic patterns and pathogenetic implications of IGHV gene usage in chronic lymphocytic leukemia: lesson of the IGHV3-21 gene. Blood. 2005;105:1678–85.Google Scholar
  28. 28.
    Gustavsson E, Sernbo S, Andersson E, Brennan DJ, Dictor M, Jerkeman M, et al. SOX11 expression correlates to promoter methylation and regulates tumor growth in hematopoietic malignancies. Mol Cancer. 2010;9:187.Google Scholar
  29. 29.
    Stilgenbauer S, Bullinger L, Lichter P, Döhner H, German CLL Study Group (GCLLSG). Chronic lymphocytic leukemia. Genetics of chronic lymphocytic leukemia: genomic aberrations and V(H) gene mutation status in pathogenesis and clinical course. Leukemia. 2002;16:993–1007.Google Scholar
  30. 30.
    Vasconcelos Y, de Vos J, Vallat L, Rème T, Lalanne AI, Wanherdrick K, et al. Gene expression profiling of chronic lymphocytic leukemia can discriminate cases with stable disease and mutated Ig genes from those with progressive disease and unmutated Ig genes. Leukemia. 2005;19:2002–5.Google Scholar
  31. 31.
    Navarro A, Clot G, Royo C, Jares P, Hadzidimitriou A, Agathangelidis A, et al. Molecular subsets of mantle cell lymphoma defined by the IGHV mutational status and SOX11 expression have distinct biologic and clinical features. Cancer Res. 2012;72:5307–16.Google Scholar
  32. 32.
    Fernandez V, Salamero O, Espinet B, Solé F, Royo C, Navarro A, et al. Genomic and gene expression profiling defines indolent forms of mantle cell lymphoma. Cancer Res. 2010;70:1408–18.Google Scholar
  33. 33.
    Chen YH, Gao J, Fan G, Peterson LC. 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. Mod Pathol. 2010;23:105–12.CrossRefPubMedGoogle Scholar
  34. 34.
    Sinner D, Kordich JJ, Spence JR, Opoka R, Rankin S, Lin SC, et al. Sox17 and Sox4 differentially regulate beta-catenin/T-cell factor activity and proliferation of colon carcinoma cells. Mol Cell Biol. 2007;27:7802–15.Google Scholar
  35. 35.
    Murugan S, Shan J, Kühl SJ, Tata A, Pietilä I, Kühl M et al. WT1 and Sox11 regulate synergistically the promoter of the Wnt4 gene that encodes a critical signal for nephrogenesis. Exp Cell Res. 2012;318:1134–45.CrossRefPubMedGoogle Scholar
  36. 36.
    MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17:9–26.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Lu D, Zhao Y, Tawatao R, Cottam HB, Sen M, Leoni LM, et al. Activation of the Wnt signaling pathway in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2004;101:3118–23.Google Scholar
  38. 38.
    Gutierrez Jr A, Tschumper RC, Wu X, Shanafelt TD, Eckel-Passow J, Huddleston PM, et al. LEF-1 is a prosurvival factor in chronic lymphocytic leukemia and is expressed in the preleukemic state of monoclonal B cell lymphocytosis. Blood. 2010;116:2975–83.Google Scholar
  39. 39.
    Molica S, Cutrona G, Vitelli G, Mirabelli R, Molica M, Digiesi G, et al. Markers of increased angiogenesis and their correlation with biological parameters identifying high-risk patients in early B-cell chronic lymphocytic leukemia. Leuk Res. 2007;31:1575–8.CrossRefPubMedGoogle Scholar
  40. 40.
    Frater JL, Kay NE, Goolsby CL, Crawford SE, Dewald GW, Peterson LC. Dysregulated angiogenesis in B-chronic lymphocytic leukemia: morphologic, immunohistochemical, and flow cytometric evidence. Diagn Pathol. 2008;3:16.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Xia Y, Lu RN, Li J. Angiogenic factors in chronic lymphocytic leukemia. Leuk Res. 2012;36:1211–7.CrossRefPubMedGoogle Scholar
  42. 42.
    Maffei R, Fiorcari S, Bulgarelli J, Rizzotto L, Martinelli S, Rigolin GM, et al. Endothelium-mediated survival of leukemic cells and angiogenesis-related factors are affected by lenalidomide treatment in chronic lymphocytic leukemia. Exp Hematol. 2014;42:126–36.CrossRefPubMedGoogle Scholar
  43. 43.
    Palomero J, Vegliante MC, Rodríguez ML, Eguileor A, Castellano G, Planas-Rigol E, et al. SOX11 promotes tumor angiogenesis through transcriptional regulation of PDGFA in mantle cell lymphoma. Blood 2014; 124: 2235-47.Google Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Alejandro Roisman
    • 1
  • Carmen Stanganelli
    • 2
  • Virginia Palau Nagore
    • 1
  • Guillermo Videla Richardson
    • 3
  • María Elida Scassa
    • 3
  • Raimundo Fernando Bezares
    • 4
  • María Cabrejo
    • 5
  • Irma Slavutsky
    • 1
  1. 1.Laboratorio de Genética de Neoplasias Linfoides, Instituto de Medicina ExperimentalCONICET-Academia Nacional de MedicinaBuenos AiresArgentina
  2. 2.División Patología Molecular, Instituto de Investigaciones Hematológicas “Mariano R. Castex”Academia Nacional de MedicinaBuenos AiresArgentina
  3. 3.Laboratorio de Investigación Aplicada a Neurociencias-(LIAN)Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia-FLENIBuenos AiresArgentina
  4. 4.Servicio de HematologíaHospital General de Agudos “Dr Teodoro Álvarez”Buenos AiresArgentina
  5. 5.Servicio de Hematología, Sanatorio Municipal “Dr. Julio Méndez”Buenos AiresArgentina

Personalised recommendations