Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2

Alexander Ungewickell; Aparna Bhaduri; Eon Rios; Jason Reuter; Carolyn S. Lee; Angela Mah; Ashley Zehnder; Robert Ohgami; Shashikant Kulkarni; Randall Armstrong; Wen Kai Weng; Dita Gratzinger; Mahkam Tavallaee; Alain Rook; Michael Snyder; Youn Kim; Paul A. Khavari

doi:10.1038/ng.3370

Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2

Alexander Ungewickell, Aparna Bhaduri, Eon Rios, Jason Reuter, Carolyn S. Lee, Angela Mah, Ashley Zehnder, Robert Ohgami, Shashikant Kulkarni, Randall Armstrong, Wen Kai Weng, Dita Gratzinger, Mahkam Tavallaee, Alain Rook, Michael Snyder, Youn Kim, Paul A. Khavari

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188 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1056-1060
Number of pages	5
Journal	Nature genetics
Volume	47
Issue number	9
DOIs	https://doi.org/10.1038/ng.3370
State	Published - Aug 27 2015
Externally published	Yes

ASJC Scopus subject areas

Genetics

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Ungewickell, A., Bhaduri, A., Rios, E., Reuter, J., Lee, C. S., Mah, A., Zehnder, A., Ohgami, R., Kulkarni, S., Armstrong, R., Weng, W. K., Gratzinger, D., Tavallaee, M., Rook, A., Snyder, M., Kim, Y., & Khavari, P. A. (2015). Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2. Nature genetics, 47(9), 1056-1060. https://doi.org/10.1038/ng.3370

Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2. / Ungewickell, Alexander; Bhaduri, Aparna; Rios, Eon; Reuter, Jason; Lee, Carolyn S.; Mah, Angela; Zehnder, Ashley; Ohgami, Robert; Kulkarni, Shashikant; Armstrong, Randall; Weng, Wen Kai; Gratzinger, Dita; Tavallaee, Mahkam; Rook, Alain; Snyder, Michael; Kim, Youn; Khavari, Paul A.

In: Nature genetics, Vol. 47, No. 9, 27.08.2015, p. 1056-1060.

Research output: Contribution to journal › Article › peer-review

Ungewickell, A, Bhaduri, A, Rios, E, Reuter, J, Lee, CS, Mah, A, Zehnder, A, Ohgami, R, Kulkarni, S, Armstrong, R, Weng, WK, Gratzinger, D, Tavallaee, M, Rook, A, Snyder, M, Kim, Y & Khavari, PA 2015, 'Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2', Nature genetics, vol. 47, no. 9, pp. 1056-1060. https://doi.org/10.1038/ng.3370

Ungewickell, Alexander ; Bhaduri, Aparna ; Rios, Eon ; Reuter, Jason ; Lee, Carolyn S. ; Mah, Angela ; Zehnder, Ashley ; Ohgami, Robert ; Kulkarni, Shashikant ; Armstrong, Randall ; Weng, Wen Kai ; Gratzinger, Dita ; Tavallaee, Mahkam ; Rook, Alain ; Snyder, Michael ; Kim, Youn ; Khavari, Paul A. / Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2. In: Nature genetics. 2015 ; Vol. 47, No. 9. pp. 1056-1060.

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title = "Genomic analysis of mycosis fungoides and S{\'e}zary syndrome identifies recurrent alterations in TNFR2",

abstract = "Mycosis fungoides and S{\'e}zary 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 S{\'e}zary 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.",

author = "Alexander Ungewickell and Aparna Bhaduri and Eon Rios and Jason Reuter and Lee, {Carolyn S.} and Angela Mah and Ashley Zehnder and Robert Ohgami and Shashikant Kulkarni and Randall Armstrong and Weng, {Wen Kai} and Dita Gratzinger and Mahkam Tavallaee and Alain Rook and Michael Snyder and Youn Kim and Khavari, {Paul A.}",

note = "Funding Information: 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. Publisher Copyright: {\textcopyright} 2015 Nature America, Inc. All rights reserved.",

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Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2

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