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J Invest Dermatol. 2018 May;138(5):1116-1125. doi: 10.1016/j.jid.2017.10.028. Epub 2017 Nov 8.

Role of Dysregulated Cytokine Signaling and Bacterial Triggers in the Pathogenesis of Cutaneous T-Cell Lymphoma.

Author information

1
Department of Pathology, New York University School of Medicine, New York, New York, USA.
2
Department of Medicine, Division of Hematology-Oncology, New York University School of Medicine, New York, New York, USA.
3
Department of Basic Science and Craniofacial Biology, NYU College of Dentistry, New York, New York, USA.
4
Department of Pathology, New York University School of Medicine, New York, New York, USA; Office of Collaborative Science, New York University School of Medicine, New York, New York, USA.
5
Department of Pathology, New York University School of Medicine, New York, New York, USA; Laura and Isaac Perlmutter Cancer Institute, New York University School of Medicine, New York, New York, USA.
6
The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York, USA.
7
Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, Florida, USA.
8
Department of Pathology, Brigham and Women's Hospital; Boston, Massachusetts, USA.
9
Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
10
Department of Medicine, Division of Hematology-Oncology, New York University School of Medicine, New York, New York, USA; Department of Pathology, Brigham and Women's Hospital; Boston, Massachusetts, USA.
11
Department of Pathology, New York University School of Medicine, New York, New York, USA; Laura and Isaac Perlmutter Cancer Institute, New York University School of Medicine, New York, New York, USA. Electronic address: sergei.koralov@med.nyu.edu.

Abstract

Cutaneous T-cell lymphoma is a heterogeneous group of lymphomas characterized by the accumulation of malignant T cells in the skin. The molecular and cellular etiology of this malignancy remains enigmatic, and what role antigenic stimulation plays in the initiation and/or progression of the disease remains to be elucidated. Deep sequencing of the tumor genome showed a highly heterogeneous landscape of genetic perturbations, and transcriptome analysis of transformed T cells further highlighted the heterogeneity of this disease. Nonetheless, using data harvested from high-throughput transcriptional profiling allowed us to develop a reliable signature of this malignancy. Focusing on a key cytokine signaling pathway previously implicated in cutaneous T-cell lymphoma pathogenesis, JAK/STAT signaling, we used conditional gene targeting to develop a fully penetrant small animal model of this disease that recapitulates many key features of mycosis fungoides, a common variant of cutaneous T-cell lymphoma. Using this mouse model, we show that T-cell receptor engagement is critical for malignant transformation of the T lymphocytes and that progression of the disease is dependent on microbiota.

PMID:
29128259
PMCID:
PMC5912980
[Available on 2019-05-01]
DOI:
10.1016/j.jid.2017.10.028

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