Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

High-resolution chromatin immunoprecipitation (ChIP) sequencing reveals novel binding targets and prognostic role for SOX11 in mantle cell lymphoma

Abstract

Sex determining region Y-box 11 (SOX11) expression is specific for mantle cell lymphoma (MCL) as compared with other non-Hodgkin’s lymphomas. However, the function and direct-binding targets of SOX11 in MCL are largely unknown. We used high-resolution chromatin immunoprecipitation sequencing to identify the direct target genes of SOX11 in a genome-wide, unbiased manner and elucidate its functional significance. Pathway analysis identified WNT, PKA and TGF-beta signaling pathways as significantly enriched by SOX11-target genes. Quantitative chromatin immunoprecipitation sequencing and promoter reporter assays confirmed that SOX11 directly binds to individual genes and modulates their transcription activities in these pathways in MCL. Functional studies using RNA interference demonstrate that SOX11 directly regulates WNT in MCL. We analyzed SOX11 expression in three independent well-annotated tissue microarrays from the University of Wisconsin (UW), Karolinska Institute and British Columbia Cancer Agency. Our findings suggest that high SOX11 expression is associated with improved survival in a subset of MCL patients, particularly those treated with intensive chemotherapy. Transcriptional regulation of WNT and other biological pathways affected by SOX11-target genes may help explain the impact of SOX11 expression on patient outcomes.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

References

  1. Witzig TE . Current treatment approaches for mantle-cell lymphoma. J Clin Oncol 2005; 23: 6409–6414.

    CAS  Article  PubMed  Google Scholar 

  2. Bodrug SE, Warner BJ, Bath ML, Lindeman GJ, Harris AW, Adams JM . Cyclin D1 transgene impedes lymphocyte maturation and collaborates in lymphomagenesis with the myc gene. EMBO J 1994; 13: 2124–2130.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 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: 1408–1418.

    CAS  Article  PubMed  Google Scholar 

  4. 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 23: 105–112.

    Article  PubMed  Google Scholar 

  5. 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: 1563–1568.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Dy P, Penzo-Mendez 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: 3101–3117.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Sock E, Rettig SD, Enderich J, Bosl 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: 6635–6644.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Wang X, Bjorklund S, Wasik AM, Grandien A, Andersson P, Kimby E et al. Gene expression profiling and chromatin immunoprecipitation identify DBN1, SETMAR and HIG2 as direct targets of SOX11 in mantle cell lymphoma. PLoS One 2010; 5: e14085.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Harley VR, Lovell-Badge R, Goodfellow PN . Definition of a consensus DNA binding site for SRY. Nucleic Acids Res 1994; 22: 1500–1501.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Badis G, Berger MF, Philippakis AA, Talukder S, Gehrke AR, Jaeger SA et al. Diversity and complexity in DNA recognition by transcription factors. Science 2009; 324: 1720–1723.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Ishitani T, Ninomiya-Tsuji J, Matsumoto K . Regulation of lymphoid enhancer factor 1/T-cell factor by mitogen-activated protein kinase-related nemo-like kinase-dependent phosphorylation in Wnt/β-catenin signaling. Mol Cell Biol 2003; 23: 1379–1389.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Labbé E, Letamendia A, Attisano L . Association of Smads with lymphoid enhancer binding factor 1/T cell-specific factor mediates cooperative signaling by the transforming growth factor-β and Wnt pathways. Proc Natl Acad Sci USA 2000; 97: 8358–8363.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Zhang M, Wang M, Tan X, Li TF, Zhang YE, Chen D . Smad3 prevents β-catenin degradation and facilitates β-catenin nuclear translocation in chondrocytes. J Biol Chem 2010; 285: 8703–8710.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Sakamoto I, Kishida S, Fukui A, Kishida M, Yamamoto H, Hino S et al. A novel β-catenin-binding protein inhibits β-catenin-dependent TCF activation and axis formation. J Biol Chem 2000; 275: 32871–32878.

    CAS  Article  PubMed  Google Scholar 

  15. Stamos JL, Weis WI . The β-catenin destruction complex. Cold Spring Harb Perspect Biol 2013; 5: 1–16.

    Article  Google Scholar 

  16. Latres E, Chiaur DS, Pagano M . The human F box protein b-Trcp associates with the Cul1/Skp1 complex and regulates the stability of β-catenin. Oncogene 1999; 18: 849–854.

    CAS  Article  PubMed  Google Scholar 

  17. SI Matsuzawa, JC Reed . Siah-1, SIP, and Ebi collaborate in a novel pathway for β-catenin degradation linked to p53 responses. Mol Cell 2001; 7: 915–926.

    Article  Google Scholar 

  18. Gelebart P, Anand M, Armanious H, Peters AC, Dien Bard J, Amin HM et al. Constitutive activation of the Wnt canonical pathway in mantle cell lymphoma. Blood 2008; 112: 5171–5179.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Kimura Y, Arakawa F, Kiyasu J, Miyoshi H, Yoshida M, Ichikawa A et al. The Wnt signaling pathway and mitotic regulators in the initiation and evolution of mantle cell lymphoma: gene expression analysis. Int J Oncol 2013; 43: 457–468.

    CAS  Article  PubMed  Google Scholar 

  20. Riabowol K, Draetta G, Brizuela L, Vandre D, Beach D . The cdc2 kinase is a nuclear protein that is essential for mitosis in mammalian cells. Cell 1989; 57: 393–401.

    CAS  Article  PubMed  Google Scholar 

  21. Draetta G, Beach D . Activation of cdc2 protein kinase during mitosis in human cells: cell cycle-dependent phosphorylation and subunit rearrangement. Cell 1988; 54: 17–26.

    CAS  Article  PubMed  Google Scholar 

  22. Rhind N, Russell P . Signaling pathways that regulate cell division. Cold Spring Harb Perspect Biol 2012; 4: 1–15.

    Article  Google Scholar 

  23. Asciutti S, Akiri G, Grumolato L, Vijayakumar S, Aaronson SA . Diverse mechanisms of Wnt activation and effects of pathway inhibition on proliferation of human gastric carcinoma cells. Oncogene 2011; 30: 956–966.

    CAS  Article  PubMed  Google Scholar 

  24. Romaguera JE, Fayad LE, Feng L, Hartig K, Weaver P, Rodriguez MA et al. Ten-year follow-up after intense chemoimmunotherapy with Rituximab-HyperCVAD alternating with Rituximab-high dose methotrexate/cytarabine (R-MA) and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma. Brit J Haematol 2010; 150: 200–208.

    CAS  Google Scholar 

  25. Greiner TC, Moynihan MJ, Chan WC, Lytle DM, Pedersen A, Anderson JR et al. p53 mutations in mantle cell lymphoma are associated with variant cytology and predict a poor prognosis. Blood 1996; 87: 4302–4310.

    CAS  PubMed  Google Scholar 

  26. Pan X, Zhao J, Zhang WN, Li HY, Mu R, Zhou T et al. Induction of SOX4 by DNA damage is critical for p53 stabilization and function. Proc Natl Acad Sci USA 2009; 106: 3788–3793.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Wiestner A, Tehrani M, Chiorazzi M, Wright G, Gibellini F, Nakayama K et al. Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival. Blood 2007; 109: 4599–4606.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Clevers H . Wnt/β-catenin signaling in development and disease. Cell 2006; 127: 469–480.

    CAS  Article  PubMed  Google Scholar 

  29. Chung EJ, Hwang SG, Nguyen P, Lee S, Kim JS, Kim JW et al. Regulation of leukemic cell adhesion, proliferation, and survival by beta-catenin. Blood 2002; 100: 982–990.

    CAS  Article  PubMed  Google Scholar 

  30. van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A et al. The β-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 2002; 111: 241–250.

    CAS  Article  PubMed  Google Scholar 

  31. Giles RH, van Es JH, Clevers H . Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta 2003; 1653: 1–24.

    CAS  PubMed  Google Scholar 

  32. Taketo MM . Shutting down Wnt signal-activated cancer. Nat Genet 2004; 36: 320–322.

    CAS  Article  PubMed  Google Scholar 

  33. Grumolato L, Liu G, Haremaki T, Mungamuri SK, Mong P, Akiri G et al. β-catenin-independent activation of TCF1/LEF1 in human hematopoietic tumor cells through Interaction with ATF2 transcription factors. PLoS Genet 2013; 9: e1003603.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Zorn AM, Barish GD, Williams BO, Lavender P, Klymkowsky MW, Varmus HE . Regulation of Wnt signaling by Sox proteins: XSox17 alpha/beta and XSox3 physically interact with beta-catenin. Mol Cell 1999; 4: 487–498.

    CAS  Article  PubMed  Google Scholar 

  35. Kormish JD, Sinner D, Zorn AM . Interactions between SOX factors and Wnt/β-catenin signaling in development and disease. Dev Dyn 2010; 239: 56–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 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: 7802–7815.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Murugan S, Shan J, Kuhl 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: 1134–1145.

    CAS  Article  PubMed  Google Scholar 

  38. Vegliante MC, Palomero J, Pérez-Galán P, Roué G, Castellano G, Navarro A et al. SOX11 regulates PAX5 expression and blocks terminal B-cell differentiation in aggressive mantle cell lymphoma. Blood 2013; 121: 2175–2185.

    CAS  Article  PubMed  Google Scholar 

  39. Carvajal-Cuenca A, Sua LF, Silva NM, Pittaluga S, Royo C, Song JY et al. In situ mantle cell lymphoma: clinical implications of an incidental finding with indolent clinical behavior. Haematologica 2012; 97: 270–278.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Leshchenko VV, Kuo PY, Shaknovich R, Yang DT, Gellen T, Petrich A et al. Genomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma. Blood 2010; 116: 1025–1034.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Vegliante MC, Royo C, Palomero J, Salaverria I, Balint B, Martín-Guerrero I et al. Epigenetic activation of SOX11 in lymphoid neoplasms by histone modifications. PloS One 2011; 6: e21382.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 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  PubMed  Google Scholar 

  43. Geisler CH, Kolstad A, Laurell A, Jerkeman M, Räty R, Andersen NS et al. Nordic MCL2 trial update: six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC+autologous stem-cell support: still very long survival but late relapses do occur. Brit J Haematol 2012; 158: 355–362.

    CAS  Article  Google Scholar 

  44. 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: 1510–1517.

    CAS  Article  PubMed  Google Scholar 

  45. Sernbo S, Gustavsson E, Brennan DJ, Gallagher WM, Rexhepaj E, Rydnert F et al. The tumour suppressor SOX11 is associated with improved survival among high grade epithelial ovarian cancers and is regulated by reversible promoter methylation. BMC Cancer 2011; 11: 405.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. de Bont JM, Kros JM, Passier MM, Reddingius RE, Sillevis Smitt PA, Luider TM et al. Differential expression and prognostic significance of SOX genes in pediatric medulloblastoma and ependymoma identified by microarray analysis. Neuro-oncology 2008; 10: 648–660.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 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: 139–144.

    CAS  PubMed  Google Scholar 

  48. Kridel R, Meissner B, Rogic S, Boyle M, Telenius A, Woolcock B et al. Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. Blood 2012; 119: 1963–1971.

    CAS  Article  PubMed  Google Scholar 

  49. Lee JY, Elmer HL, Ross KR, Kelley TJ . Isoprenoid-mediated control of SMAD3 expression in a cultured model of cystic fibrosis epithelial cells. Am J Respir Cell Mol Biol 2004; 31: 234–240.

    CAS  Article  PubMed  Google Scholar 

  50. Giannopoulou EG, Elemento O . An integrated ChIP-seq analysis platform with customizable workflows. BMC Bioinformatics 2011; 12: 277.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Heinz S, Benner C, Spann N, Bertolino E, Lin YC, Laslo P et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell 2010; 38: 576–589.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Wu TD, Nacu S . Fast and SNP-tolerant detection of complex variants and splicing in short reads. Bioinformatics 2010; 26: 873–881.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B . Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nature 2008; 5: 621–628.

    CAS  Google Scholar 

  54. Storey JD, Tibshirani R . Statistical significance for genome-wide studies. Proc Natl Acad Sci USA 2003; 100: 9440–9445.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. Oberley MJ, Rajguru SA, Zhang C, Kim K, Shaw GR, Grindle KM et al. Immunohistochemical evaluation of MYC expression in mantle cell lymphoma. Histopathology 2013; 63: 499–508.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the Epigenomics cores at Weil Cornell Medical College and Albert Einstein College of Medicine for the service support in next generation sequencing. We would also like to thank Eugenia (Jenny) Giannopoulou, PhD, and Olivier Elemento, PhD, for the assistance in ChIP-seq analysis and Chris Benner, PhD, for the support in motif analysis. We are grateful for Stuart A Aaronson, MD, for the expert consultation on WNT signaling pathway and the DN-TCF4 construct and Thomas J Kelly, MD, PhD for the SMAD3 reporter construct. This project was funded in part by the Chemotherapy Foundation (SP), Gabrielle's Angel Foundation (SP), Leukemia and Lymphoma Society Translational Research Project Grant (SP), Paul Calabresi Career Development Award K12-CA132783-01 (SP), the Swedish Cancer Society (BS), the Swedish Research Council (BS), the Cancer Society in Stockholm (BS), the Karolinska Institutet Funds (BS) and the Stockholm County Council (BS). DTY is supported by the Clinical and Translational Science Award (CTSA) program, previously through the National Center for Research Resources grant 1UL1RR025011, and now by the National Center for Advancing Translational Sciences (NCATS), grant 9U54TR000021 (DTY), grant P30 CA014520 from the National Cancer Institute and Forward Lymphoma (DTY).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to S Parekh.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

This study was presented in part (publication number: 895) at the 54th Annual Meeting of the American Society of Hematology, Atlanta, VA, USA on 11 December 2012.

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kuo, PY., Leshchenko, V., Fazzari, M. et al. High-resolution chromatin immunoprecipitation (ChIP) sequencing reveals novel binding targets and prognostic role for SOX11 in mantle cell lymphoma. Oncogene 34, 1231–1240 (2015). https://doi.org/10.1038/onc.2014.44

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2014.44

This article is cited by

Search

Quick links