Abstract

Mycosis fungoides and Sézary syndrome comprise the majority of cutaneous T cell lymphomas (CTCLs), disorders notable for their clinical heterogeneity that can present in skin or peripheral blood. Effective treatment options for CTCL are limited, and the genetic basis of these T cell lymphomas remains incompletely characterized1. Here we report recurrent point mutations and genomic gains of TNFRSF1B, encoding the tumor necrosis factor receptor TNFR2, in 18% of patients with mycosis fungoides and Sézary syndrome. Expression of the recurrent TNFR2 Thr377Ile mutant in T cells leads to enhanced non-canonical NF-κB signaling that is sensitive to the proteasome inhibitor bortezomib. Using an integrative genomic approach, we additionally discovered a recurrent CTLA4-CD28 fusion, as well as mutations in downstream signaling mediators of these receptors.

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Acknowledgements

We thank A. Alizadeh, H. Chang, S. Artandi, L. Boxer, D. Webster and J. Kovalski for presubmission review of the manuscript. We thank all the patients who generously participated in this study. This work was supported by the Office of Research and Development of the US Department of Veterans Affairs and by US National Institutes of Health (NIH) grant R01CA142635 awarded to P.A.K. A.U. was supported by US NIH grant F32CA168091 and by the American Society of Hematology Research Training Award for Fellows. A.B. received support from US NIH grant F310CA180408. E.R. received support from the Dermatology Foundation. The studies were generously supported by the Haas Family Foundation and the Drs. Martin and Dorothy Spatz Charitable Foundation.

Author information

Author notes

    • Alexander Ungewickell
    •  & Aparna Bhaduri

    These authors contributed equally to this work.

Affiliations

  1. Program in Epithelial Biology, Stanford University, Stanford, California, USA.

    • Alexander Ungewickell
    • , Aparna Bhaduri
    • , Eon Rios
    • , Carolyn S Lee
    • , Angela Mah
    • , Ashley Zehnder
    •  & Paul A Khavari
  2. Division of Hematology, Stanford University, Stanford, California, USA.

    • Alexander Ungewickell
  3. Department of Genetics, Stanford University, Stanford, California, USA.

    • Jason Reuter
    •  & Michael Snyder
  4. Department of Pathology, Stanford University, Stanford, California, USA.

    • Robert Ohgami
    •  & Dita Gratzinger
  5. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Shashikant Kulkarni
  6. Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Shashikant Kulkarni
  7. Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Shashikant Kulkarni
  8. Division of Blood and Marrow Transplantation, Stanford University, Stanford, California, USA.

    • Randall Armstrong
    •  & Wen-Kai Weng
  9. Multidisciplinary Cutaneous Lymphoma Program, Stanford University, Stanford, California, USA.

    • Mahkam Tavallaee
    •  & Youn Kim
  10. Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Alain Rook
  11. Veterans Affairs Palo Alto Healthcare System, Palo Alto, California, USA.

    • Paul A Khavari

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Contributions

A.U. and A.B. designed and executed experiments, analyzed data and wrote the manuscript. E.R., C.S.L., J.R., A.M., A.Z., R.O., S.K., R.A., W.-K.W. and D.G. helped execute experiments, analyzed data and contributed to the design of experimentation. M.T. performed clinical data analysis. M.S. helped design experiments. A.R. and Y.K. provided clinical data and analysis. P.A.K. designed experiments, analyzed data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Paul A Khavari.

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DOI

https://doi.org/10.1038/ng.3370

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