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

Linghua Wang; Xiao Ni; Kyle R. Covington; Betty Y. Yang; Jessica Shiu; Xiang Zhang; Liu Xi; Qingchang Meng; Timothy Langridge; Jennifer Drummond; Lawrence A. Donehower; Harshavardhan Doddapaneni; Donna M. Muzny; Richard A. Gibbs; David A. Wheeler; Madeleine Duvic

doi:10.1038/ng.3444

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

Linghua Wang, Xiao Ni, Kyle R. Covington, Betty Y. Yang, Jessica Shiu, Xiang Zhang, Liu Xi, Qingchang Meng, Timothy Langridge, Jennifer Drummond, Lawrence A. Donehower, Harshavardhan Doddapaneni, Donna M. Muzny, Richard A. Gibbs, David A. Wheeler, Madeleine Duvic

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

264 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1426-1434
Number of pages	9
Journal	Nature genetics
Volume	47
Issue number	12
DOIs	https://doi.org/10.1038/ng.3444
State	Published - Dec 1 2015
Externally published	Yes

ASJC Scopus subject areas

Genetics

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Wang, L., Ni, X., Covington, K. R., Yang, B. Y., Shiu, J., Zhang, X., Xi, L., Meng, Q., Langridge, T., Drummond, J., Donehower, L. A., Doddapaneni, H., Muzny, D. M., Gibbs, R. A., Wheeler, D. A., & Duvic, M. (2015). Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes. Nature genetics, 47(12), 1426-1434. https://doi.org/10.1038/ng.3444

Wang, L, Ni, X, Covington, KR, Yang, BY, Shiu, J, Zhang, X, Xi, L, Meng, Q, Langridge, T, Drummond, J, Donehower, LA, Doddapaneni, H, Muzny, DM, Gibbs, RA, Wheeler, DA & Duvic, M 2015, 'Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes', Nature genetics, vol. 47, no. 12, pp. 1426-1434. https://doi.org/10.1038/ng.3444

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title = "Genomic profiling of S{\'e}zary syndrome identifies alterations of key T cell signaling and differentiation genes",

abstract = "S{\'e}zary 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 S{\'e}zary 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 S{\'e}zary syndrome and suggest potential targets for new therapies.",

author = "Linghua Wang and Xiao Ni and Covington, {Kyle R.} and Yang, {Betty Y.} and Jessica Shiu and Xiang Zhang and Liu Xi and Qingchang Meng and Timothy Langridge and Jennifer Drummond and Donehower, {Lawrence A.} and Harshavardhan Doddapaneni and Muzny, {Donna M.} and Gibbs, {Richard A.} and Wheeler, {David A.} and Madeleine Duvic",

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AU - Zhang, Xiang

AU - Xi, Liu

AU - Meng, Qingchang

AU - Langridge, Timothy

AU - Drummond, Jennifer

AU - Donehower, Lawrence A.

AU - Doddapaneni, Harshavardhan

AU - Muzny, Donna M.

AU - Gibbs, Richard A.

AU - Wheeler, David A.

AU - Duvic, Madeleine

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AB - 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.

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

Abstract

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