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.

  • Article
  • Published:

Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes

Nature Genetics volume 47, pages 1426–1434 (2015)Cite this article

Subjects

Abstract

Sézary syndrome is a rare leukemic form of cutaneous T cell lymphoma characterized by generalized redness, scaling, itching and increased numbers of circulating atypical T lymphocytes. It is rarely curable, with poor prognosis. Here we present a multiplatform genomic analysis of 37 patients with Sézary syndrome that implicates dysregulation of cell cycle checkpoint and T cell signaling. Frequent somatic alterations were identified in TP53, CARD11, CCR4, PLCG1, CDKN2A, ARID1A, RPS6KA1 and ZEB1. Activating CCR4 and CARD11 mutations were detected in nearly one-third of patients. ZEB1, encoding a transcription repressor essential for T cell differentiation, was deleted in over one-half of patients. IL32 and IL2RG were overexpressed in nearly all cases. Our results demonstrate profound disruption of key signaling pathways in Sézary syndrome and suggest potential targets for new therapies.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Somatic genomic alterations identified in Sézary syndrome.
Figure 2: Significant somatic mutation and copy number alterations.
Figure 3: Dysregulated signaling pathways.
Figure 4: Increased IL32 gene and IL-32 protein expression.
Figure 5: Survival and correlation analysis.

Similar content being viewed by others

References

  1. Campbell, J.J., Clark, R.A., Watanabe, R. & Kupper, T.S. Sézary syndrome and mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for their distinct clinical behaviors. Blood 116, 767–771 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Girardi, M., Heald, P.W. & Wilson, L.D. The pathogenesis of mycosis fungoides. N. Engl. J. Med. 350, 1978–1988 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Kim, Y.H., Liu, H.L., Mraz-Gernhard, S., Varghese, A. & Hoppe, R.T. Long-term outcome of 525 patients with mycosis fungoides and Sézary syndrome: clinical prognostic factors and risk for disease progression. Arch. Dermatol. 139, 857–866 (2003).

    PubMed  Google Scholar 

  4. Olsen, E. et al. Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood 110, 1713–1722 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Herne, K.L., Talpur, R., Breuer-McHam, J., Champlin, R. & Duvic, M. Cytomegalovirus seropositivity is significantly associated with mycosis fungoides and Sézary syndrome. Blood 101, 2132–2136 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Talpur, R., Bassett, R. & Duvic, M. Prevalence and treatment of Staphylococcus aureus colonization in patients with mycosis fungoides and Sézary syndrome. Br. J. Dermatol. 159, 105–112 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Agar, N.S. et al. Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J. Clin. Oncol. 28, 4730–4739 (2010).

    Article  PubMed  Google Scholar 

  8. Scarisbrick, J.J. et al. Prognostic factors, prognostic indices and staging in mycosis fungoides and Sézary syndrome: where are we now? Br. J. Dermatol. 170, 1226–1236 (2014).

    Article  CAS  PubMed  Google Scholar 

  9. Talpur, R. et al. Long-term outcomes of 1,263 patients with mycosis fungoides and Sézary syndrome from 1982 to 2009. Clin. Cancer Res. 18, 5051–5060 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. Vidulich, K.A., Talpur, R., Bassett, R.L. & Duvic, M. Overall survival in erythrodermic cutaneous T-cell lymphoma: an analysis of prognostic factors in a cohort of patients with erythrodermic cutaneous T-cell lymphoma. Int. J. Dermatol. 48, 243–252 (2009).

    Article  PubMed  Google Scholar 

  11. Kim, E.J. et al. Immunopathogenesis and therapy of cutaneous T cell lymphoma. J. Clin. Invest. 115, 798–812 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ni, X., Zhang, C., Talpur, R. & Duvic, M. Resistance to activation-induced cell death and bystander cytotoxicity via the Fas/Fas ligand pathway are implicated in the pathogenesis of cutaneous T cell lymphomas. J. Invest. Dermatol. 124, 741–750 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Batista, D.A. et al. Multicolor fluorescence in situ hybridization (SKY) in mycosis fungoides and Sézary syndrome: search for recurrent chromosome abnormalities. Genes Chromosom. Cancer 45, 383–391 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Caprini, E. et al. Identification of key regions and genes important in the pathogenesis of Sézary syndrome by combining genomic and expression microarrays. Cancer Res. 69, 8438–8446 (2009).

    Article  CAS  PubMed  Google Scholar 

  15. Mao, X., Chaplin, T. & Young, B.D. Integrated genomic analysis of Sézary syndrome. Genet. Res. Int. 2011, 980150 (2011).

    PubMed  PubMed Central  Google Scholar 

  16. Mao, X. et al. Molecular cytogenetic characterization of Sézary syndrome. Genes Chromosom. Cancer 36, 250–260 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Vermeer, M.H. et al. Novel and highly recurrent chromosomal alterations in Sézary syndrome. Cancer Res. 68, 2689–2698 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Braun, F.C.M. et al. Tumor suppressor TNFAIP3 (A20) is frequently deleted in Sézary syndrome. Leukemia 25, 1494–1501 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. Laharanne, E. et al. CDKN2A-CDKN2B deletion defines an aggressive subset of cutaneous T-cell lymphoma. Mod. Pathol. 23, 547–558 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. Lamprecht, B. et al. The tumour suppressor p53 is frequently nonfunctional in Sézary syndrome. Br. J. Dermatol. 167, 240–246 (2012).

    Article  CAS  PubMed  Google Scholar 

  21. Vaqué, J.P. et al. PLCG1 mutations in cutaneous T-cell lymphomas. Blood 123, 2034–2043 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. Duvic, M. & Foss, F.M. Mycosis fungoides: pathophysiology and emerging therapies. Semin. Oncol. 34, S21–S28 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Horwitz, S.M. Novel therapies for cutaneous T-cell lymphomas. Clin. Lymphoma Myeloma 8 (suppl. 5), S187–S192 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Venkatarajan, S. & Duvic, M. Sézary syndrome: an overview of current and future treatment options. Expert Opin. Orphan Drugs 2, 3 (2014).

    Google Scholar 

  25. Wang, L. et al. Novel somatic and germline mutations in intracranial germ cell tumours. Nature 511, 241–245 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lawrence, M.S. et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505, 495–501 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wheeler, D.A. & Wang, L. From human genome to cancer genome: the first decade. Genome Res. 23, 1054–1062 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Alexandrov, L.B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Clark, R.A. Resident memory T cells in human health and disease. Sci. Transl. Med. 7, 269rv1 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wu, X.S., Lonsdorf, A.S. & Hwang, S.T. Cutaneous T-cell lymphoma: roles for chemokines and chemokine receptors. J. Invest. Dermatol. 129, 1115–1119 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yoshie, O. & Matsushima, K. CCR4 and its ligands: from bench to bedside. Int. Immunol. 27, 11–20 (2015).

    Article  CAS  PubMed  Google Scholar 

  32. Ni, X. et al. Reduction of regulatory T cells by Mogamulizumab, a defucosylated anti–CC chemokine receptor 4 antibody, in patients with aggressive/refractory mycosis fungoides and Sézary syndrome. Clin. Cancer Res. 21, 274–285 (2015).

    Article  CAS  PubMed  Google Scholar 

  33. Duvic, M. et al. Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated patients with cutaneous T-cell lymphoma. Blood 125, 1883–1889 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nakagawa, M. et al. Gain-of-function CCR4 mutations in adult T cell leukemia/lymphoma. J. Exp. Med. 211, 2497–2505 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Matsumoto, R. et al. Phosphorylation of CARMA1 plays a critical role in T cell receptor–mediated NF-κB activation. Immunity 23, 575–585 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Hara, H. et al. The MAGUK family protein CARD11 is essential for lymphocyte activation. Immunity 18, 763–775 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Wang, D. et al. A requirement for CARMA1 in TCR-induced NF-κB activation. Nat. Immunol. 3, 830–835 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Lohr, J.G. et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc. Natl. Acad. Sci. USA 109, 3879–3884 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Lenz, G. et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 319, 1676–1679 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Dereure, O., Portales, P., Clot, J. & Guilhou, J.J. Decreased expression of Fas (APO-1/CD95) on peripheral blood CD4+ T lymphocytes in cutaneous T-cell lymphomas. Br. J. Dermatol. 143, 1205–1210 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Jones, C.L. et al. Downregulation of Fas gene expression in Sézary syndrome is associated with promoter hypermethylation. J. Invest. Dermatol. 130, 1116–1125 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Ungewickell, A. et al. Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2. Nat. Genet. 47, 1056–1060 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Choi, J. et al. Genomic landscape of cutaneous T cell lymphoma. Nat. Genet. 47, 1011–1019 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Postigo, A.A. & Dean, D.C. Independent repressor domains in ZEB regulate muscle and T-cell differentiation. Mol. Cell. Biol. 19, 7961–7971 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Higashi, Y. et al. Impairment of T cell development in δEF1 mutant mice. J. Exp. Med. 185, 1467–1479 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Nakahata, S., Yamazaki, S., Nakauchi, H. & Morishita, K. Downregulation of ZEB1 and overexpression of Smad7 contribute to resistance to TGF-β1–mediated growth suppression in adult T-cell leukemia/lymphoma. Oncogene 29, 4157–4169 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Hidaka, T. et al. Down-regulation of TCF8 is involved in the leukemogenesis of adult T-cell leukemia/lymphoma. Blood 112, 383–393 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Blais, A. & Dynlacht, B.D. E2F-associated chromatin modifiers and cell cycle control. Curr. Opin. Cell Biol. 19, 658–662 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Nagl, N.G. Jr., Wang, X., Patsialou, A., Van Scoy, M. & Moran, E. Distinct mammalian SWI/SNF chromatin remodeling complexes with opposing roles in cell-cycle control. EMBO J. 26, 752–763 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Nam, H.J. et al. The ERK-RSK1 activation by growth factors at G2 phase delays cell cycle progression and reduces mitotic aberrations. Cell. Signal. 20, 1349–1358 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. Freeman, G.J. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027–1034 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Okazaki, T., Chikuma, S., Iwai, Y., Fagarasan, S. & Honjo, T. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat. Immunol. 14, 1212–1218 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Suga, H. et al. The role of IL-32 in cutaneous T-cell lymphoma. J. Invest. Dermatol. 134, 1428–1435 (2014).

    Article  CAS  PubMed  Google Scholar 

  54. Ohmatsu, H. et al. IL32 is progressively expressed in mycosis fungoides independent of helper T-cell 2 and helper T-cell 9 polarization. Cancer Immunol. Res. 2, 890–900 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kim, K.H. et al. Interleukin-32 monoclonal antibodies for immunohistochemistry, Western blotting, and ELISA. J. Immunol. Methods 333, 38–50 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. Huether, R. et al. The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes. Nat. Commun. 5, 3630 (2014).

    Article  CAS  PubMed  Google Scholar 

  57. Vega, F. et al. Clonal heterogeneity in mycosis fungoides and its relationship to clinical course. Blood 100, 3369–3373 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. Jackow, C.M. et al. Association of erythrodermic cutaneous T-cell lymphoma, superantigen-positive Staphylococcus aureus, and oligoclonal T-cell receptor Vβ gene expansion. Blood 89, 32–40 (1997).

    CAS  PubMed  Google Scholar 

  59. Tan, R.S., Butterworth, C.M., McLaughlin, H., Malka, S. & Samman, P.D. Mycosis fungoides—a disease of antigen persistence. Br. J. Dermatol. 91, 607–616 (1974).

    Article  CAS  PubMed  Google Scholar 

  60. Bradford, P.T., Devesa, S.S., Anderson, W.F. & Toro, J.R. Cutaneous lymphoma incidence patterns in the United States: a population-based study of 3884 cases. Blood 113, 5064–5073 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Takashima, A. Establishment of fibroblast cultures. Curr. Protoc. Cell Biol. Ch. 2, Unit 2.1 (2001).

  62. Lawrence, M.S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. DeLuca, D.S. et al. RNA-SeQC: RNA-seq metrics for quality control and process optimization. Bioinformatics 28, 1530–1532 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).

    Article  CAS  PubMed  Google Scholar 

  65. Roberts, A., Pimentel, H., Trapnell, C. & Pachter, L. Identification of novel transcripts in annotated genomes using RNA-Seq. Bioinformatics 27, 2325–2329 (2011).

    Article  CAS  PubMed  Google Scholar 

  66. McPherson, A. et al. deFuse: an algorithm for gene fusion discovery in tumor RNA-Seq data. PLoS Comput. Biol. 7, e1001138 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank J. Hu, M. Wang, Y. Han, H. Chao and M.G. Evans for their excellent technical support. We thank L. Sandra for help with sample intake and J. Jayaseelan for project management. We thank W. Hale, D. Kalra, S. Dugan-Perez and J. Watt for their kind help with data submission. Special thanks is given to D. Burgess and M. Chase from Roche NimbleGen for their great help with the design and fast delivery of the custom capture array. This work was supported by research funding from the National Human Genome Research Institute (NHGRI; grant 5U54HG003273) and the Cancer Prevention Research Institute of Texas (CPRIT; grant RP121018) to D.A.W., the Drs. Martin and Dorothy Spatz Charitable Foundation (grant 00005840), the Blanche Bender Professorship in Cancer Research and the MD Anderson Cancer Center Core Grant (grant CA16672) to M.D.

Author information

Authors and Affiliations

  1. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA

    Linghua Wang, Kyle R Covington, Liu Xi, Qingchang Meng, Jennifer Drummond, Harshavardhan Doddapaneni, Donna M Muzny, Richard A Gibbs & David A Wheeler

  2. Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Xiao Ni, Betty Y Yang, Jessica Shiu, Xiang Zhang, Timothy Langridge & Madeleine Duvic

  3. Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA

    Lawrence A Donehower

Authors
  1. Linghua Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiao Ni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kyle R Covington
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Betty Y Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jessica Shiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Liu Xi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qingchang Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Timothy Langridge
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jennifer Drummond
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Lawrence A Donehower
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Harshavardhan Doddapaneni
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Donna M Muzny
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Richard A Gibbs
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. David A Wheeler
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Madeleine Duvic
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

L.W. conducted the major bioinformatics analyses of the multiplatform data, and wrote and revised the manuscript. X.N. contributed to performing the research, data interpretation and manuscript preparation. K.R.C. contributed to mutation signature analysis. B.Y.Y. and J.S. contributed to performing the research. X.Z. collected tumor specimens and performed DNA and RNA extraction, and immunoblot assays. L.X. and J.D. contributed to the RNA-seq and whole-exome sequencing pipeline. Q.M. contributed to the fusion gene validation experiments. T.L. helped with the serum and ELISA assays. D.M.M. and H.D. managed the production pipeline of exome, RNA-seq and SNP array analysis. L.A.D. contributed the somatic mutation significance analysis. R.A.G. contributed to revision of the manuscript. D.A.W., M.D. and L.W. conceived the study and supervised the research. D.A.W. and M.D. also contributed to the writing and revision of the manuscript. M.D. recruited, consented, staged, characterized and cared for the patients and supervised the skin biopsies.

Corresponding authors

Correspondence to David A Wheeler or Madeleine Duvic.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–12. (PDF 8255 kb)

Supplementary Tables 1–17

Supplementary Tables 1–17. (XLSX 3207 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, L., Ni, X., Covington, K. et al. Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes. Nat Genet 47, 1426–1434 (2015). https://doi.org/10.1038/ng.3444

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.3444

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer