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 characterized. 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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Base Sequence
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Bortezomib / pharmacology
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CD28 Antigens / genetics
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CTLA-4 Antigen / genetics
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Cell Line, Tumor
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DNA Mutational Analysis
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Drug Resistance, Neoplasm
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Gene Expression
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Gene Expression Regulation, Neoplastic
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Genetic Predisposition to Disease
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Genome-Wide Association Study
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Genomics
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Humans
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Mycosis Fungoides / genetics*
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Oncogene Proteins, Fusion / genetics
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Point Mutation
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Receptors, Tumor Necrosis Factor, Type II / genetics*
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Receptors, Tumor Necrosis Factor, Type II / metabolism
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Sezary Syndrome / genetics*
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Signal Transduction
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Skin Neoplasms / genetics*
Substances
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Antineoplastic Agents
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CD28 Antigens
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CTLA-4 Antigen
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CTLA4 protein, human
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Oncogene Proteins, Fusion
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Receptors, Tumor Necrosis Factor, Type II
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Bortezomib