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

2015; Nature Portfolio; Volume: 47; Issue: 9 Linguagem: Inglês

10.1038/ng.3370

1546-1718

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

Toxin Mechanisms and Immunotoxins

Paul Khavari and colleagues report genomic analyses of cutaneous T cell lymphomas. They identify recurrent point mutations and genomic gains of TNFRSF1B, encoding the tumor necrosis factor receptor TNFR2, in 18% of tumors and show that expression of a recurrent TNFR2 mutant in T cells leads to enhanced non-canonical NF-κB signaling that is sensitive to the proteasome inhibitor bortezomib. 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.